Management of oxidative stress and inflammation in cardiovascular diseases: mechanisms and challenges

Abstract

Cardiovascular diseases (CVDs) have diverse physiopathological mechanisms with interconnected oxidative stress and inflammation as one of the common etiologies which result in the onset and development of atherosclerotic plaques. In this review, we illustrate this strong crosstalk between oxidative stress, inflammation, and CVD. Also, mitochondrial functions underlying this crosstalk, and various approaches for the prevention of redox/inflammatory biological impacts will be illustrated. In part, we focus on the laboratory biomarkers and physiological tests for the evaluation of oxidative stress status and inflammatory processes. The impact of a healthy lifestyle on CVD onset and development is displayed as well. Furthermore, the differences in oxidative stress and inflammation are related to genetic susceptibility to cardiovascular diseases and the variability in the assessment of CVDs risk between individuals; Omics technologies for measuring oxidative stress and inflammation will be explored. Finally, we display the oxidative stress-related microRNA and the functions of the redox basis of epigenetic modifications.

Introduction

Cardiovascular diseases (CVDs) are considered as one of the leading reasons for global death (Chen et al. 2019). CVDs involve several pathologies such as disorders of the coronary and peripheral arteries as well as cerebrovascular diseases. Many of these diseases were related to atherosclerosis development (Choi et al. 2018). Furthermore, they may cause stroke, myocardial infarction (MI), and ischemia/reperfusion (I/R) injury. Other types of CVDs include atrial fibrillation (AF), chronic heart failure (CHF), and complications of cardiovascular diabetes. Dyslipidemia, smoking, hypertension, diabetes mellitus, and chronic kidney diseases (CKD) are well-known risk factors for CVDs which ultimately lead to oxidative stress and stimulate inflammation (Sárközy et al. 2018). Inflammation is one of the key intermediate pathways involved in the development of cardiovascular disorders (Koene et al. 2016).

In this regard, in hypertension, oxidative stress promotes endothelial dysfunction, vascular remodeling, and inflammation in hypertension which leads to vascular damage (Montezano et al. 2015). As inflammation is contributing to atherogenesis disease progression, anti-inflammatory treatments may offer a solution to cardiovascular problems (Welsh et al. 2017). Given the clear associations between high reactive oxygen species (ROS), oxidative stress, and heart disease, ROS has become an attractive treatment target to enhance cell antioxidant capabilities and ROS detoxification in several drug-based strategies (Peoples et al. 2019).

CVDs are a multicausal problem, in this regard, we focus on the causes related to inflammation and oxidative stress and how to manage them by considering risk factors, basic and advanced assessment, and treatment using healthy diet components and supplements. Challenges are also displayed with possible solutions. Methodology to find the article via PubMed last 10 years using keywords as MESH terms. Understanding the role of inflammation and oxidative stress is essential for increasing the chance of success during cardiovascular disease treatment. Moreover, new markers Exploration will also provide an opportunity to understand the mechanisms and new treatments for CVDs.

There are many basic laboratory markers (Tousoulis et al. 2012) and physiological tests (Lu et al. 2016) that help in the diagnosis and therapy of CVDs. Also, micro ribonucleic acids (miRNAs) are a type of non-coding RNAs that are intensively studied and have a significant impact on heart status by protein translation inhibition or target mRNA degradation so changes in their expression help in the diagnosis of CVDs (Dong et al. 2019). Besides, omics approaches such as redox transcriptomics, proteomics, and metabolomics as well as DNA methylation analysis could be used as tools for identifying clinical biomarkers; the integration of such data will increase cardiovascular disease understanding and speed up the identification of new diagnostics or therapeutic targets (Huertas-Vazquez et al. 2019).

In this paper, we will review the various CVDs risk factors that lead to oxidative stress and inflammation highlighting different cellular and molecular mechanisms with focusing on the assessment markers of oxidative stress status and inflammatory processes such as oxidative-stress-related microRNA as well as the redox basis of epigenetic modifications. Also, we will demonstrate the link between mitochondrial dysfunction and CVDs and how atherosclerotic plaques were formed. Furthermore, the mechanism of different antioxidant and anti-inflammatory agents to manage oxidative stress and inflammation with an overall description of other risk factors and their management.

Cellular and molecular mechanisms of oxidative stress and inflammation in CVDs

Nuclear factor erythroid 2 (Nrf2) is a pivotal CVD protection molecule that reduces oxidative stress, mitochondrial dysfunction, and inflammation. Following oxidative stress, Nrf2 is activated leading to its nuclear translocation and activation which subsequently regulates the transcription of a group of cardioprotective molecules such as hemeoxygenase-1 (HO-1), NADPH quinone oxidoreductase-1 (NQO1), and nuclear factor-κB (NF-κB). HO-1 expression is concomitant with glutathione S-transferases (GST) and superoxide dismutase (SOD) elevation leading to inhibition of oxidative stress (Uddin et al. 2020). NQO1 was known to regulate cardiac metabolism and reduce injury in inflammation with increasing resistance against oxidative stress, apoptosis, and atherosclerosis. Nuclear factor-kappa light chain-enhancer of activated B cells (NF-κB) restraining by Nrf2 can protect the heart and vasculature against injury (Jiang et al. 2016) as described in Fig. 1.

Fig. 1

The pivotal role of nuclear factor erythroid 2 molecule in reducing oxidative stress, mitochondrial dysfunction, and inflammation which leads to CVDs protection. Nrf2: nuclear factor erythroid 2; HO- HO-1: hemeoxygenase-1; NQO: NADPH quinone oxidoreductase-1; NF-κB: nuclear factor-κB; GST: glutathione S-transferases; SOD: superoxide dismutase. ROS: reactive oxygen species; RNS: reactive nitrogen species

For the progression of CVDs, oxidative stress is considered as the key risk factor and is contributed to the excessive production of free radicals or ROS and the inability of cells to detoxify them (Powers et al. 2010), leading to a shift in the redox state of some organelles such as mitochondria and the nucleus. Subsequently, some macromolecules such as lipids, proteins, and DNA will be extremely damaged by oxidative stress (Choi et al. 2018) as shown in Fig. 1. ROS are usually formed during aerobic metabolism (Holterman et al. 2015). The most common ROS are hydroxyl radical (^-.OH) and superoxide anions (O₂^.-) as well as hydrogen peroxide (H₂O₂) and considered the essential cellular redox status effectors (Loperena and Harrison 2017).

On the other hand, inflammation is another key significant risk factor for the pathological progression of CVDs (Choi et al. 2018). Two transcription factors in the inflammatory response pathways assist in CVD progression as key modulators: nuclear factor kappa light chain- enhancer of activated B cells (NF- κB) and hypoxia-inducible factor-1 alpha (HIF-1α) where the central inflammatory signaling cascade mediates by NF-κB (Nardinocchi et al. 2010). In the state of unstimulated cells, NF-κB heterodimer (p65/p50) is interacted with a class of inhibitory proteins called IκB (IκBα, -β, and -ε) and trapped in the cytosol so inflammation induction is inhibited. On the other hand, in the state of the stimulated cells, several stimuli enhance NF-κB activation, for instance, interleukin-1(IL-1), tumor necrosis factor-α (TNF-α), activators of protein kinase C (PKC), oxidants, and ionizing radiation. These stimuli induce phosphorylation and subsequent IκB protein degradation via the ubiquitin-proteasome system. Therefore, free NF-κB can translocate to the nucleus resulting in gene expression of pro-inflammatory genes such as chemokines, cytokines as well as adhesion molecules, which subsequently stimulate the inflammation process (Rao et al. 2017) as summarized in Fig. 2.

Fig. 2

Regulation of inflammation process by NF- κB. NF- κB: nuclear factor kappa-B; IκB: inhibitor of nuclear factor kappa-B; TNF-α: tumor necrosis factor-alpha, IL-1: interleukin-1; IL-6: interleukin-6; PKC: protein kinase C

Many arterial wall pathological conditions are considered vascular diseases that may induce obstruction of blood flow. Such pathological conditions comprise atherosclerosis, arterial remodeling, restenosis, and thrombosis (Hulsmans and Holvoet 2010).

Atherosclerosis, the principal reason for CVD deaths, is a condition of chronic inflammation. Also, it is well known that the accumulation of lipids and/or fibrous materials and leucocytes in blood vessels and the arteries’ deepest layer is characteristic of atherosclerosis (Libby et al. 2010); this leads to the formation of fatty streak lesions called plaque in the vessel wall. Over time, an atherosclerotic plaque hardens and becomes more fibrous, and accumulates calcium mineral which results in the arteries narrowing and blood flow restriction. As a consequence, fatty plaques rupture, a blood clot, or a thrombus formed with an additional restriction of oxygen-rich blood flow to the body organs (Wiciński et al. 2020). Furthermore, the cumulative risk of atherogenic damage is increased by pathological disorders associated with prothrombotic, pro-inflammatory, and metabolic conditions (Clevenger 2016).

Oxidative stress does not only damage macromolecules directly and irreversibly but also disturbs the key redox-dependent signaling pathways of the arterial wall (Craige et al. 2015). In this context, nitric oxide (NO) was known to regulate cardiovascular homeostasis. The well-defined mechanism by which oxidative stress can enhance vascular disease may be through disturbance of the vasoprotection induced by NO signaling pathway (Murphy et al. 2016). NO is inactivated through reaction with superoxide anions and formation peroxynitrite (ONOO¯) leading to suppression of its anti-inflammatory and vasodilator functions (Stasch et al. 2011). Also, ONOO¯ is a powerful oxidant that causes oxidative stress by oxidation of antioxidants of small molecular size compounds such as tetrahydrobiopterin, cysteine, and glutathione (Stasch et al. 2011) (Fig. 3).

Fig. 3

Disturbance of vasoprotection induced by nitric oxide signaling pathway. GSH: reduced glutathione; eNOS: endothelial nitric oxide synthase; SOD: superoxide dismutase; GR: glutathione reductase

Besides, ONOO¯ can also oxidize and inhibit antioxidant enzymes, such as glutathione reductase, superoxide dismutase (SOD), and glutaredoxin (Stasch et al. 2011), as well as dimethylargininase-1 which metabolize asymmetric dimethylarginine, an endogenous endothelial NOS (eNOS) inhibitor (Murphy et al. 2016). Consequently, NO receptor dysfunction is caused by oxidative stress because of the binding of NO to the soluble guanylyl cyclase (sGC) haem group and further oxidation of its Fe²⁺ state to the Fe³⁺ state leading to a significant reduction in sGC affinity for NO (Stasch et al. 2011).

NO synthesis is catalyzed by nitric oxide synthase (NOS) three isoforms derived from the expression of discrete genes. The enzyme isoforms are called neuronal NOS (nNOS), and inducible NOS (iNOS), as well as endothelial NOS (eNOS) and, are encoded by NOS1, NOS2, and NOS3 genes respectively (Farah et al. 2018). It has been found that hypertension and endothelial dysfunction were caused by a decrease in the level of endothelial NO; this is in line with Coats and Jain study which indicated that the production of NO by nNOS regulates the release of catecholamine following the stimulation of the electrical adrenergic nerve, either in vitro or in vivo. Higher catecholamine levels are also related to the pathological condition of heart failure (Coats and Jain 2017). Besides, endothelial cells produce eNOS for NO generation after stimulation of muscarinic cholinergic receptors and adrenergic in the myocardium. It has been shown that acute and chronic β-adrenergic activation affects eNOS activity (Coats and Jain 2017) (see Fig. 4). eNOS enzyme activity is regulated by G-protein coupled receptors, modulators of AKT kinase, or calcium flux which are compartimentalized in caveolae or recruited to caveolae or nearby membrane regions upon activation (Heiss and Dirsch 2014).

Fig. 4

The activity, expression, and uncoupling of eNOS in acute β-adrenergic (b) and chronic β-adrenergic activation (c) compared to normal condition (a). eNOS: endothelial nitric oxide synthase; ROS, reactive oxygen species; NO: nitric oxide

Moreover, ROS may enhance vascular remodeling and inflammation. Most adverse effects of ROS on the arterial wall are attributed to CVDs (Kleniewska et al. 2012). It is well documented that the oxidation of major signaling phosphatases and kinases as well as the activation of NF-κB and subsequently stimulate the endothelial adhesion molecules expression. This in turn induced both proliferation and migration of vascular smooth muscle cells (VSMCs) which are the main cells in the arterial wall (Hai and Zuo 2016).

ROS also promotes the vascular remodeling by oxidation and subsequent activation of matrix metalloproteinases (MMPs) (Santillo et al. 2015) which are a group of zinc-dependent proteases that degrade many extracellular matrix (ECM) components and mediate remodeling in both physiological and pathological processes (Sampieri and Orozco-Ortega 2018). Most MMPs play a major role in the formation, remodeling, and angiogenesis of blood vessels by regulating the functions or behaviors of stem/progenitor and vascular cells (Chen et al. 2013).

The mitochondria play a key role in most cellular biology in eukaryotes. For example, in the cardiovascular system, it is mostly involved in both anabolic and catabolic metabolism as well as the initiation of the inflammatory reaction, regulation of intracellular Ca²⁺ homeostasis, and control of various pathways regarding regulated cell death (RCD) (Mehta et al. 2017). Furthermore, the mitochondrial system has been found to constantly undergo a tight quality control mechanism (Delbridge et al. 2017) known as mitophagy that is needed to optimally detect damaged mitochondria and delivering them to the lysosome for degradation (Harper et al. 2018).

In the crosstalk between mitochondrial function and redox biology, it is well known that ROS are normally produced from mitochondria during oxidative phosphorylation and physiological levels of ROS are involved in the regulation of various cardiovascular processes such as myocardial metabolic functions and vessel endothelial permeability (Shadel and Horvath 2015). Although mitochondrial dysfunction is generally linked to excessive production of ROS with low cellular antioxidant defenses, this will lead to oxidative damage to macromolecules resulting in local inflammation and initiation of many variants of RCD including the mitochondrial permeability transition driven (MPT) regulated necrosis and ferroptosis (Bonora et al. 2015). In agreement with these findings, it was showed that increasing ROS generation in the myocardium causes contractile failure as well as structural damage and ultimately leading to MI (Shirakawa et al. 2019).

In the presence of mitochondrial SOD2 and extramitochondrial SOD1, O₂^.- is converted into O₂ and H₂O₂. Then, there are two fates for the metabolism of H₂O₂; the first one is catalyzed by catalase (CAT) results in the formation of H₂O. The second fate was found to be catalyzed by glutathione peroxidase (GPx) which reduces H₂O₂ to water with the oxidation of reduced glutathione (GSH). Besides, in the presence of Cu¹⁺ or Fe²⁺, H₂O₂ could be converted into OH^• and OH^– in the Fenton reaction (Bonora et al. 2019). Physiological ROS levels were found to control many biological processes such as autophagy, intracellular signaling, adaptation to hypoxia, and both adaptive and innate immunity (Sena and Chandel 2012). Nonetheless, ROS can cause extensive damage to macromolecules such as proteins, DNA, lipids when exceeding the capacities of endogenous antioxidants and subsequently results in RCD or cell senescence (Fig. 5).

Fig. 5

Mitochondria function and redox biology. GSH: reduced glutathione; SOD: superoxide dismutase; GPx: glutathione peroxidase; CAT: catalase

NO controls cardiovascular function via two different mechanisms: the first one indirectly through increasing sGC activity and subsequent activation of its downstream substrate called protein kinase G, and the second one directly via the S-nitrosylation of proteins (Maron et al. 2013). Lipophilic NO properties prefer paracrine signaling by its migration from endothelial cells to cardiomyocytes, VSMCs, and vessel lumen, while autocrine signaling of NO takes place mostly in heart myocytes (Amelio et al. 2015). Hemoglobin-α (Hb-α) has been shown to regulate paracrine NO diffusion in the cardiac endothelial junction (Straub et al. 2012). The mechanism of endothelial Hb-α in NO signaling showed that Hb-α Fe³⁺ state induces this signaling and when converted to Hb-α Fe²⁺ by endothelial cytochrome b5 reductase 3, the NO signaling is inhibited. Therefore, the inhibition of endothelial cytochrome b5 reductase 3 could offer a therapeutic approach for increasing the bioactivity of NO in small arteries (Straub et al. 2012).

In the relationship between ROS and hypertension, oxidative stress stimulates vascular inflammation, endothelial dysfunction, enhanced functional, and structural remodeling causing increased blood pressure and peripheral resistance (Brito et al. 2015). NADPH oxidase (NOX) is transmembrane proteins with many subunits and in the membranes of smooth muscle cells, vascular endothelial cells, and fibroblasts, it induces the production of superoxide by transfer a single electron from NADPH to molecular O₂, which belongs to ROS. Consequently, NOX enzymes have a crucial role in various CVDs pathophysiology (Touyz and Briones 2011).

Molecular processes regarding ROS affect hypertension development involves activation of vascular redox-sensitive signaling pathways, where the vasodilator NO is decreased with increased production of ROS. ROS (O₂^.- and H₂O₂) induce tyrosine kinases, mitogen-activated protein kinases (MAPK), Rho kinase, transcription factors including NF-κB, Activator protein-1 (AP-1), and HIF-1. Also, they suppress protein tyrosine phosphatases, increase intracellular free Ca²⁺ concentration, and increase proinflammatory and protooncogene gene expression as well as activity (Fig. 6) (Al Ghouleh et al. 2011). At the vascular level, these intracellular signaling alterations can subsequently result in endothelial dysfunction, decreased vasodilation, elevated contraction, and structural remodeling leading to enhanced peripheral resistance and hypertension (Touyz and Briones 2011). Maintaining normal O₂ homeostasis via O₂ sensing by the effect of ROS on HIF-1 regulation. In pathological conditions, ROS are involved in inflammation, endothelial dysfunction, cell activation, proliferation and migration, and extracellular matrix deposition, fibrosis, angiogenesis, and vascular remodeling (Gupta et al. 2016).

Fig. 6

The mechanism of elevated NOX activity in inducing inflammation which as subsequence causes cardiovascular diseases

In the kidney, redox-sensitive pathway activation is implicated with glomerular damage, proteinuria, water and sodium retention, and nephron function loss which are crucial in the development of hypertension (Sasser et al. 2014). Centrally produced ROS by NADPH oxidase (NOX) in the hypothalamic and circumventricular organs are involved in central control of blood pressure elevation, partially through sympathetic outflow (Purushothaman et al. 2011). Although oxidative stress may involve the hypertension pathophysiology and damage of the associated target organ, it is not the sole cause of hypertension. The previous studies demonstrate that inhibitors of ROS bioavailability decline, but do not normalize the blood pressure in hypertension models (Montezano and Touyz 2014).

Risk factors for CVDs

Also, cardiovascular diseases are considered as both primary and secondary diseases, where many other disorders cause it, for instance, obesity, arterial hypertension, hypercholesterolemia, smoking, sedentary and an unhealthy lifestyle, aging, alcoholism, hyperglycemia, both type 1 and type 2 diabetes, and the metabolic syndrome (Fig. 7) (Rückert et al. 2012). Regarding vascular function, these metabolism disorders are viewed as significant risk factors in congestive heart failure and cardiac dysfunction progress (Rückert et al. 2012). Besides, CKD is a public health problem that accelerates the pathology of CVD (Sárközy et al. 2018) and it is well shown as the leading cause of morbidity and mortality in patients with CKD. The elevated incidence of CVD in CKD patients is only partially represented by the higher prevalence of traditional risk factors in these patients such as aging, dyslipidemia, hypertension, diabetes, smoking, and obesity (Subbiah et al. 2016) (Fig. 7).

Fig. 7

The most common cardiovascular disease risk factors

The accumulation of uremic toxins in CKD including inorganic phosphate, para-cresyl sulfate, indoxyl sulfate, and fibroblast growth factor 23 (Six et al. 2020) is due to impairment of renal clearance (Nuhu and Bhandari 2018). Also, the uremic milieu comprises several cardiac risk factors that give respond to a distinct cardiac pathology termed uremic cardiomyopathy with the prevalence of left ventricular hypertrophy (Foley et al. 2010). The respiratory function of mitochondria in uraemia is affected by increased exposure to mitochondria toward calcium and stress-induced oxidation that may enhance the increased susceptibility of the uremic heart to I/R injury (Taylor et al. 2015).

Furthermore, the association between CKD and unique cardiomyopathy is characterized by both cellular and structural remodeling, and an increased risk of ischemia (Semple et al. 2012). Besides, the inflammation occurs by the accumulation of uremic toxins (Six et al. 2020) as well as oxidative stress, ROS induction of a decline in NO production (Ishigami et al. 2016), anemia (Pisani et al. 2015). This accumulation accelerates the pathology of CVD, such as heart failure, which directly causes kidney dysfunction. In considering the progression of CKD, part of the mechanism is via oxidant-induced damage to the glomerular basement membrane (Pisani et al. 2015). This complex association recognized cardiorenal syndrome (Guo et al. 2017). Patients with CKD are in a constant inflammatory case caused by several factors, including the uremic state, malnutrition, chronic volume overload, increased infection, metabolic acidosis, and autonomic dysfunction (Nuhu and Bhandari 2018).

Genetic composition which is concerned with the initiation and development of cardiovascular diseases can also be associated with oxidant stress (He and Zuo 2015). Regarding NOX, NOX1 and NOX2 were found to be associated with the induction of Angiotensin II for eNOS uncoupling with reduced tetrahydrobiopterin (BH4) levels (Sheehan et al. 2011). Also, angiotensin II causes vasoconstriction as well as an increase in both blood pressure, vascular muscle proliferation, and is involved in the ROS development cycle, resulting in vascular tissue damage (Kemp et al. 2014). Besides, NOX4 which is expressed by endothelial cells and VSMCs could produce H₂O₂ (Incalza et al. 2018) and subsequently increased activation of eNOS, 5- adenosine monophosphate-activated protein kinase-α, vascular endothelial growth factor (VEGF) receptor 2, and p38MAPK pathways which are vital for angiogenesis. p47phox is an essential NOX cytosolic subunit and its knockout causes a reduction in the generation of ROS, NO production via PI3K-AKT- eNOS (Mittal et al. 2014). The polymorphism of p22phox rs4673 has been established as a 1.53-fold risk for coronary artery disease (CAD) by affecting the p22phox protein function (Mazaheri et al. 2017).

nNOS (Gimbrone Jr and García-Cardeña 2016) and eNOS (Ponnuswamy et al. 2012) were found to protect from atherogenesis, whereas increased expression of iNOS leading to excessive NO production which participates in aggravating the development of atherosclerotic plaques (Förstermann et al. 2017).

The eNOS gene has been well investigated in three functional polymorphisms: the first is single nucleotide polymorphism (SNP) called 786 T > C (rs2070744) at 5′ flanking eNOS gene region was found to decline the activity of its gene promoter approximately by 50%, a missense mutation 894G >T (Glu298Asp, rs1799983) in exon 7 influences NO levels by affecting the activity of eNOS activity, and intron 4 a 27-bp VNTR (4b/a) polymorphism and is due to splicing of small interference RNA pre-mRNA processing of eNOS leading to suppression of the expression of eNOS (Group 2014). Also, three SNPs are significantly associated with CAD in ancestries of Middle Eastern, European, Asian, Asian–Indian, and African (Glu298Asp) (Rai et al. 2014). Glu298Asp and 4b / a are the strongest in the Middle East, while T786-C showed higher CAD risk among Asian subjects (Rai et al. 2014).

Regarding the myeloperoxidase (MPO) gene, two SNPs named -129G/A and -463G/A have been reported to influence transcription factor specificity protein1 (SP1) and thus affecting the expression of MPO (Mishra et al. 2011). Also, they have been shown to raise the risk for CAD by 1.94 and 1.53 respectively (Mishra et al. 2011). Furthermore, the incidence of hypertension increased by 1.31- and 1.69-fold with the xanthine oxidase (XO) SNPs, e.g., rs11904439 and rs148756340, respectively (Scheepers et al. 2016). Other XO SNPs have also increased hypertension in Japanese populations, i.e., 47686C > T, 69901A > C, and 67873A > C and 69901A > C was found to be substantially associated with atherosclerosis of the carotid artery (Johnson et al. 2018). Moreover, it has been documented that carriers of cyclooxygenase COX-2 rs5277 C-allele increased the risk for negative cerebrovascular and cardiac events in particular for CAD (Liu et al. 2017b). Also, the multivessel CAD incidence of the G-765C COX2 polymorphism (rs20417) has been reduced (Rostoff et al. 2014).

Also, in the promoter region of the arachidonate 5-lipoxygenase (ALOX5) gene, it has been shown that the SP1 addition/deletion polymorphism increases the risk for CAD by 4.47-folds via affecting low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels (Todur and Ashavaid 2012). The variants of ALOX15, i.e., rs2619112 GA and rs7217186 CT are increased CAD risk by 2.27- and 3.41-fold respectively (Kaur et al. 2018). Also, the haplotypes of 5-lipoxygenase-activating protein (ALOX5AP) including HapB and HapC haplotypes are found to raise the CAD risk by 1.67- and 2.41-folds, respectively (Stock et al. 2011). Moreover, the epistemic interactions of the ALOX5, ALOX5AP, and MPO were found to contribute to ischemic stroke synergistically (Liu et al. 2017a).

Plasma levels of SOD1 and SOD2 were reported to be increased in patients with CAD (Peng et al. 2016). The risk for cardiovascular disease is reportedly increased by the three SOD1 variants, called rs9974610, ars1041740, and rs10432782 (Neves et al. 2012). SOD2 V16A polymorphism raises the risk of cardiovascular disease, regardless of the glycaemic score, cholesterol, blood pressure, smoking, and age (Pourvali et al. 2016). In the presence of TT genotype, the risk for CAD was significantly associated with the SOD2 C24 T while the protective role of CC and TC genotypes was found (Pourvali et al. 2016). The polymorphism SOD3 R231G was found to impact the risk for CAD with the risk factors RG and GG genotypes leading to CAD severity and risk for MI risk by reducing the levels of α-tocopherol (Nozik-Grayck et al. 2016).

It has been documented that Pro198Leu polymorphism for GPX1 and GPX-1 activity of less than 23.9 U/g Hb leads to an increase in the risk for CAD by 2.14-fold, and 4.72- fold respectively (Wickremasinghe et al. 2016). Also, GPx1 activity was inversely associated with CAD severity and MI risk (Sies et al. 2017). The variation of GPx-1 in Pro198Leu (rs1050450 C / T) affects its activity because of the conformation of its active site structure (Klaunig et al. 2011). In diabetes mellitus type II, it has been found that both C198T GPx-1 and C609T NADP [1]: quinone oxidoreductase 1 variants participate in the risk for CAD (Ramprasath et al. 2012). Also, these variants can functionally influence the enzyme activities and in turn, the overall antioxidant capacity resulting in oxidative stress and subsequently CVD (Ramprasath et al. 2012).

Regarding heart disease, it has been well studied that a missense mutation named L55M (rs854560) affects Paraoxonase 1 (PON1) production and with the Q192R (rs662) missense mutation its catalytic efficacy is affected. The rs854560 “T-allele” results in high PON production via encoding methionine, while the one named “A-allele” decreases the activity of PON by encoding leucine. Previous studies show that AA (55LL) genotype is related to increased risk of insulin resistance, increased Intima-media thickness (IMT) carotid artery, hypertension, and increased lipoprotein involvement in the activity phospholipase A2, and thus the risk for CVDs (Ferretti et al. 2015). The genotype of PON1 named 192RR has higher enzyme activity that decreases in the following order: QQ > QR > RR, with almost extremely little PON activity in RR genotype contributing to coronary atherosclerosis (Lüersen et al. 2011).

Cigarette smoking causes the development and progression of atherosclerosis (Kunutsor et al. 2018) by stimulating endothelial dysfunction, alteration of lipid profile, and inducing inflammatory response and thrombosis (Messner and Bernhard 2014). Additionally, cigarette smoking was found to be associated with the development and progression of carotid atherosclerosis, probably partly via the inflammation pathway (Wang et al. 2018b).

In cigarette smoke, many components among 7000 chemicals are well known to mediate CVD pathophysiology (Talhout et al. 2011). Carbon monoxide, polycyclic aromatic hydrocarbons, nicotine, and heavy metals and their oxides are examples of toxic chemicals that have thorough effects on vascular endothelium, blood lipids, and clotting factors causing atherosclerosis which affects arteries (Roy et al. 2017). Also, smoking increased catecholamines release, which increased heart rate, vasoconstriction, and cardiac output as cardiovascular events (Martín-Timón et al. 2014). In short, atherogenesis starts when smoking-activated inflammatory cells bind to the endothelium weakened by smoking and accumulate below the surface of the vessel, causing chronic inflammation that promotes plaque production and growth by accumulating cells rich in cholesterol.

Other components are also involved in endothelial dysfunction, including heavy metals such as arsenic, lead, and mercury, which stimulate the oxidation of cellular proteins and may lead to structural cellular damage and endothelial dysfunction. Further endothelial dysfunction can be mediated by polycyclic aromatic hydrocarbons (Mudau et al. 2012). These compounds also promote the oxidation of LDL which is known as bad cholesterol and is proatherogenic as well as impairing the endothelial function (Mudau et al. 2012). Another lipid peroxidation product caused by tobacco is the lipoprotein acrolein, an aldehyde that reacts with HDL, making it inaccessible for the removal of cholesterol from vascular endothelium (Parthasarathy et al. 2010). This method destroys a significant mechanism used by the body to fight atherosclerosis.

Furthermore, smoking-induced thrombosis through elevated production of thrombosis factors such as thrombin, fibrinogen, and von Willebrand factor and decreased fibrinolysis, former is especially critical in CVD pathophysiology (Roy et al. 2017). Smoking is also related to increased insulin resistance and hyperinsulinemia that have been involved in diabetes and atherosclerosis acceleration (Audrain-McGovern and Benowitz 2011). Additionally, epigenetic changes of the body cells caused by cigarette smoke contribute to damage to vessel walls, thereby increasing the clotting and inflammation tendency and subsequently CVD (Vinci et al. 2013).

Furthermore, CVDs emerge from epigenetic aberrations and alterations (to improve or suppress gene expression). The epigenetic processes include methylation of DNA Cytosine–guanine-rich regions (CpG) by the action of DNA methyltransferases, post-translational histone modification performed by many enzymes such as histone methyltransferases, histone demethylases, histone acetyltransferases, and histone deacetylases (Katkam et al. 2019a).

The DNA methylation of cytosine at promoter sites is intended to downregulate expression by specifically blocking the binding of gene transcription factors thus altering the transcriptional machinery’s accessibility to DNA. DNA methyltransferases (DNMTs) such as DNMTs: DNMT1, DNMT3a, and 3b are known to catalyze DNA methylation by using S-adenosylmethionine (SAM) as a methyl donor. It has been observed that the biological processes associated with CVDs including inflammation, atherosclerosis, diabetes, and hypertension are regulated by differential methylation of the candidate genes (Duthie 2011). In CAD patients, the decreased levels of 5-methyltetrahydrofolate and SAM, and increased plasma homocysteine levels were recognized. Elevation of blood homocysteine levels was associated with decreased methylation of DNA in peripheral lymphocytes isolated from vascular disease patients (Handy et al. 2011). Also, in CAD patients, there is an increased DNA global methylation and serum homocysteine levels are higher than 12.5 μM (Milagro et al. 2013). These increased blood homocysteine levels have been shown to stimulate the expression of p66shc via the hypomethylation of its promoter resulting in increased oxidizing stress and decreased nitric oxide bioavailability (Kim et al. 2011). In the heart endothelium, the hypomethylation of eNOS is observed, while in the vascular smooth muscle cell line, it is hypermethylated. On the other hand, in response to inflammation caused by atherosclerotic plaque neointima, the expression of iNOS in most tissues is increased whereas methylation reduces its expression (Kim et al. 2013).

It has been shown that in post-translation, histones protruding N-terminal tails can be modified in a process called histone modifications (Kung et al. 2013). These modifications include methylation, acetylation, ubiquitination, phosphorylation, and sumoylation. Methylations at lysine 9, 27, and 36 on histone H3 caused a decreased gene expression, while methylations at lysine 4 and 79 on histone H3 and lysine 20 on histone H4 lead to an increased gene expression. These histone methylations are mediated through methyl group insertion by histone methyltransferases and methylation removal by histone demethylases. Acetylation of lysine on histones H3 and H4 induced an increase in gene transcription. The acetylation dynamics are also mediated by histone acetyltransferases which added acetyl groups and histone deacetylases which removed acetyl groups (Kaypee et al. 2016). In addition to affecting the transcription and gene expression, posttranslational histone modifications are also mediating apoptosis, and repair of DNA damage.

Regarding oxidative stress, it was found that alterations in cell metabolism and inflammatory responses lead to high levels of ROS and damaging DNA. In response to DNA repair, significant changes in surrounding chromatin including changes in nucleosome positioning and histone modifications are required (Vierbuchen et al. 2010). It has been shown that ROS and H₂O₂ induced epigenetic alterations, where after H₂O₂ treatment DNMT1 is more closely bound to chromatin and thus alters the methylation status of CpG regions (Tan et al. 2010). In another study, it has been shown that the upregulation of eNOS was associated with H3 and H4 histone increased acetylation in the eNOS promoter in neonatal rodent-persistent pH of the newborn model (Xu et al. 2010).

Damage to DNA sites caused by oxidative free radicals is identified by histone acetylases and deacetylases to promote repair and help improving repair protein access to the break site (Zhang et al. 2011). It has been recognized that a family of methyl-CpG binding proteins bind specifically to methylated CpGs, thus helping to repress transcription by recruiting histone-modifying proteins, including the methyl-CpG binding domain (MBD) protein family (MBD1, MBD2, MBD4, and MeCP2), Kaiso, and Kaiso-like proteins, and SRA domain proteins (e.g., SUVH9 and SUVH2) (Clapier et al. 2017). Histone methylation increases in caveolin knockout mice following I/R and is linked to the rise of histone deacetylases activity and the increase of the G9a histone methyltransferase protein level (Zhao et al. 2013).

The sirtuin (SIRT) family, consisting of seven proteins (SIRT1–SIRT7) sharing a strongly preserved catalytic domain of nicotinamide adenine dinucleotide (NAD⁺), acts as a stress adapter and epigenetic enzymes involved in the cellular events that regulate aging-related disease, cancer, and CVD (D'Onofrio et al. 2018). It was found that SIRT1, highly responsive to the cellular redox states, provides cardioprotection and vascular function maintenance by counteracting ROS effects via deacetylating multiple cellular targets (Vinciguerra et al. 2012). The redox role of the cells is regulated directly or indirectly by SIRT1, whose activity and expression can be affected by the cellular redox state by post-translation modifications (Hwang et al. 2013).

Via the deacetylation of eNOS at lysine (Lys)-496 and Lys-506, SIRT1 increases eNOS activity leading to increased production of NO, while SIRT1 knockdown has resulted in reduced production of NO and impaired endothelial-dependent vasodilation (Speakman and Mitchell 2011). At the vascular level, the physiological roles of SIRT1 and SIRT6 in the regulation of the cellular redox state are regulated by the deacetylation of multiple targets, including histones, transcription factors (FOXO, NF-kB, p53, and Nrf2), and vascular protective enzymes. SIRT6, a highly specific histone type 3 (H3) deacetylase, targets acetylated Lys-9 (acH3K9), Lys-56 (acH3K56), and Lys-18 (acH3K18). However, oxidative stress associated with various vascular dysfunctions impairs SIRT1 and SIRT6 activities on their specific targets, resulting in decreased vascular protection against oxidative stress (D'Onofrio et al. 2018).

SIRT1 and SIRT6 regulate inflammation by inhibiting the expression of inflammation-related genes, including ICAM-1, and proinflammatory cytokines, by deacetylating the p65 subunit of NF-kB. In endothelial cells, SIRT6 protects against senescence and oxidative stress by blocking the signaling of p21Cip1/Waf1 and maintaining high eNOS concentrations (D'Onofrio et al. 2018).

Basic and advanced approaches for oxidative stress and inflammation assessment in CVDs diagnosis

Biomarkers of oxidative stress status

It was reported that improving early CVD prediction is occurred by imaging (Fuster et al. 2010), genetic test (Pu et al. 2012), and biomarker assay (Tousoulis et al. 2012). The oxidative stress biomarkers are including malondialdehyde (MDA), conjugated dienes (CDs), hydroperoxides (R-OOH), F2-isoprostanes (F2-IsoPs), NOS family, MPO, uric acid (UA), protein carbonyl (PC), and trimethylamine N-oxide (TMAO) (Touyz and Briones 2011). MDA is produced from the arachidonate cycle and a principle aldehyde product of lipid peroxidation and is often measured as thiobarbituric acid (TBA) reactive substances (TBARS) (Lee et al. 2012), that is commonly used as a marker of oxidative stress in biological systems. Various studies reported that MDA and lipid hydroperoxide (LOOH) are increased in association with cardiovascular risk factors for instance diabetes mellitus and cigarette smoking (Lee et al. 2012).

Also, CDs produced because of free radical-induced autoxidation of polyunsaturated fatty acids (PUFAs) (Katerji et al. 2019), was measured as a marker of lipid peroxidation. The elevation of serum CD and TBARS levels of patients with CAD mediated by augmented production of lipid peroxidation (Speakman and Mitchell 2011). Besides, serum R-OOH as a product of lipid peroxidation induced by ROS molecules, this marker can be quantified by evaluating the derivatives of reactive oxygen metabolites assay, as described by Leufkens et al. (Leufkens et al. 2012). Also, hydroperoxides were generated from lipid oxidation and subsequently fragmented to produce many reactive intermediates, for example, prostaglandin F2α isomer F2-isoprostanes, and MDA (Nimse and Pal 2015). Experimentally and clinically, the measurement of LOOH was considered as a marker of peroxidative damage of membrane lipids and oxidative stress in vivo and they have a prognostic value in cardiovascular disease (Lee et al. 2012).

F2-IsoPs are a group of F2α-like prostaglandins, formed in vivo by non-enzymic arachidonic acid peroxidation esterified in phospholipids then hydrolyzed by platelet-activating factor acetylhydrolase to form their free acids. F2-IsoPs are chemically stable lipid peroxidation end products that are chemically stable compared to LOOH and MDA and can be detected in biological fluids, including urine, plasma, broncho-alveolar lavage, and cerebrospinal fluid as well as all human tissues (Rifkin et al. 2021). In the circulation, it was found that free F2-IsoPs are released from tissue then partially metabolized, and finally excreted into the urine. Besides, 8-Iso-prostaglandin (8-iso-PGF2α) is an abundant F2-IsoP formed in vivo in humans and has both platelet-activating and vasoconstrictive properties (Yin et al. 2011). Various studies reported that free and esterified F2-IsoPs in the plasma were significantly higher in smokers than non-smokers subjects and their levels significantly reduced after two weeks of smoking abstinence (Davies and Roberts II 2011). The level of F2-IsoPs was higher in adult subjects with high LDL or low HDL levels as well as in diabetic patients (Bouayed and Bohn 2010). Moreover, the urine F2-isoprostanes have a prognostic value in CVD, and both levels of urinary and plasma F2-IsoP levels were correlated with the number of CAD risk factors (Pompeani et al. 2014). Also, urinary 8-isoprostane was found to be a marker to known risk factors of coronary heart disease (CHD) such as smoking, diabetes mellitus, hypertension, and hypercholesterolemia (Dikalov and Ungvari 2013).

Moreover, the assessment of the NOS family is concerned with blood pressure regulation and cardiovascular function (Choi et al. 2018). NO functions as a signaling molecule that has an important role in vascular homeostasis. NO is a vasoactive substance synthesized from L-arginine by nNOS₁, iNOS_2, and eNOS₃. eNOS₃ is the vital NO synthase isoform in the vascular endothelium and consequently, it exerts critical roles in the cardiovascular system (Oliveira-Paula et al. 2017). Patients with cardiovascular risk factors (such as cigarette smoking, hypertension, hypercholesterolemia, diabetes mellitus, etc.) and patients with vascular disease show endothelial dysfunction, i.e., the failure of the endothelium to create an adequate amount of bioactive NO as well as delivery of NO-mediated vasodilation. Cardiovascular risk factors and vascular disease are also related to the enhanced production of ROS. ROS can be generated in the vessel wall by several enzymes such as xanthine oxidase, NOXs, enzymes of the mitochondrial respiratory chain, and uncoupled eNOS (Förstermann and Sessa 2012).

Also, MPO is an enzyme derived primarily from monocytes and neutrophils and plays a crucial role in leukocyte-mediated vascular injury responses. Such responses include oxidation of LDL, rendering it atherogenic and HDL, reducing its capacity to stimulate cholesterol efflux (Sugamura and Keaney Jr 2011). They are leading to a reduction in NO bioavailability, which causes endothelial dysfunction (Sugamura and Keaney Jr 2011). These effects confirmed that MPO is an actively mediated atherogenesis (Ho et al. 2013). Furthermore, in vascular disease animal studies, NOX was found to be activated in angiotensin-II induced hypertension (Lassègue et al. 2012), genetic hypertension (Förstermann et al. 2017), diabetes (Mittal et al. 2014) and hypercholesterolemia, and the expression of NOX subunits are potent in atherosclerotic arteries (Furukawa et al. 2017).

Also, it has been well documented that folate or one carbon atom pathway abolishes oxidative stress by their synergetic action with phase II enzymes of the xenobiotic metabolic pathway. Also, 5-methyltetrahydrofolate supplementation boosts the flow-mediated dilatation, an endothelial function marker (Yuyun et al. 2018). The one carbon atom metabolic pathway produces homocysteine which generates free radicals by autooxidation (Turell et al. 2013) and it has been documented that increased plasma homocysteine level is a risk factor for CAD (Ma et al. 2017).

Besides, PC content is considered as an indicator for the oxidation of proteins as well as a significant indication of oxidative stress in clinical trials in which protein backbones and amino acid residues such as threonine, lysine, proline, and arginine are oxidized by ROS molecules to generate PCs. Concerning the endogenous antioxidant biomarkers, they may be either enzymatic and non-enzymatic with the ability to eliminate ROS (Bonetta 2018) and maintain a cellular redox state. The non-enzymatic markers including peroxiredoxin (Prx), nicotinamide, metallothionein (MT); GSH. In response to animal tissue oxidative stress, the plasma GSH / GSSG ratio has also been reduced (Senoner and Dichtl 2019).

On the other side, the cell redox state is maintained by enzymatic markers such as glutathione-s-transferase (GST), (GPx), (CAT), and SOD (Bai et al. 2013) as well as heme oxygenase (HO), paraoxonase (PON), and the thioredoxin (TRX) system. Three forms of SODs were found in humans named SOD1, SOD2, and SOD3. While SOD3 is the major form in the human vascular wall and decreased superoxide concentrations by catalyzing the conversion of superoxide into hydrogen peroxide and oxygen molecule (Fatehi-Hassanabad et al. 2010). The CAT elevates the degradation of hydrogen peroxide to oxygen and water. In the preclinical model of atherosclerosis called ApoE mice, the upregulation of CAT and/or SOD expressions has been revealed to delay the atherosclerosis progression (Fatehi-Hassanabad et al. 2010). GPx has antioxidant effects by catalyzing the decrease of lipid peroxides and H₂O₂ to corresponding lipid alcohols and water via the oxidation of GSH into glutathione disulfide GSSG. Moreover, the activity of GPx isoform in red blood cells evaluated in CAD patients was shown to have a prognostic value (Sugamura and Keaney Jr 2011). Heme breakdown catalyzed by HOs to produce biliverdin that subsequently converted to bilirubin, which has an antioxidant effect and can inhibit NOX enzymes (Brandes et al. 2014).

It is well known that PON1 is a glycoprotein with antioxidant activity and its synthesis mainly takes place in the liver then it will be associated with HDL after its secretion in the blood (Meneses et al. 2019). PON1 is mainly involved in the protection of HDL and LDL against oxidative reactions and subsequently stopping its build-up or toxic products. Besides, PON1 stimulates macrophage cholesterol outflow from macrophages via HDL, reducing the differentiation between monocytes and macrophages and preventing the formation of atherosclerotic plaques (Kowalska et al. 2015).

The TRX system is a member of the oxidoreductase system existing in the VSMC and endothelial cells can scavenge ROS such as ONOO^- and H₂O₂ (Sena et al. 2013). GSTs are a multigene family of isoenzymes that are extensively expressed in humans, as well as their catalytic role in the detoxification process by conjugating GSH to a variation of harmful electrophilic compounds (Katerji et al. 2019).

Furthermore, UA, the final component of the purine nucleotide metabolism is a significant human blood antioxidant and a marker of endothelial dysfunction and inflammation (Puddu et al. 2012). Although UA acts as a potent antioxidant in plasma, it boosts oxidative stress intracellularly. In vitro and in vivo studies have indicated that UA is one of the most selective antioxidants in the plasma because it can neutralize the risky pro-oxidants for example ONOO-, OH^-, and iron-containing free radicals. Besides, it gives about 60% of the total plasma antioxidant capacity in humans (White et al. 2018). Serum UA rises, with almost 50% of patients starting hemodialysis being hyperuricemic (Kuo et al. 2013). Gathering indication refers that hyperuricemia is a risk factor for CKD that leads to renal failure (Johnson et al. 2013).

Measuring each antioxidant is complex and time-consuming and cost-effective. That is why the total antioxidant capacity (TAC) assessment in serum or plasma will provide clinicians with information about the patient’s antioxidant status as it reflects the complex interactions of antioxidants and their effect on the redox balance of the sample (Samaranayaka and Li-Chan 2011). There are many approaches used for measuring TAC (Rubio et al. 2016) and the given sample TAC value often depends on the procedure used in every specific assay. Ferric reducing the ability of serum is an established TAC estimating test, being an alteration of the ferric reducing ability assay of plasma (Lim and Lim 2013) generally utilized for TAC estimation. Additionally, the spectrophotometric 2.2-diphenyl-1-picryl-hydrazyl (DPPH) test has been reported as a more reliable way to measure TAC (Prymont-Przyminska et al. 2014). It was found that TAC is directly related to overweight/obesity indices as well as indices of metabolic syndrome laboratory measures, especially in coronary heart disease patients (Gawron-Skarbek et al. 2014).

In many studies, miRNAs were found to have important roles in cardiovascular development, pathology, repair, and regeneration and may be used to diagnose and prevent CVDs such as cardiac hypertrophy, CAD, I/R injury, and heart failure (Kreutzer et al. 2020; Kura et al. 2020). CVDs are induced and evolved by apoptosis, autophagy, necrosis, and fibrosis, as well as the proliferation and migration of cardiomyocytes, cardiac fibroblasts, endothelial cells, and VSMCs in response to increased ROS or stress stimuli. miRNAs have been reported to be employed in these processes (Colpaert and Calore 2019). Also, several miRNAs have been assigned in the cardiovascular system as regulators of oxidative stress by affecting ROS producers, antioxidant signaling mechanisms, and selected effectors of antioxidation (Gong et al. 2018).

For instance, in a study to examine whether hypercholesterolemia-induced myocardial microRNA alterations affect the production of oxidative or/ and nitrative stress and subsequent cardiac dysfunction, microRNA-25 demonstrated substantial downregulation as detected by microarray and QRT-PCR analysis. In rats fed with cholesterol, NOX4 protein was upregulated in the hearts and by downregulating microRNA-25, consequently oxidative/nitrative stress in the heart increases (Varga et al. 2013).

Intracellular ROS may also either inhibit or induce the level of miRNA expression and subsequently leading to biological effects by regulating their direct target genes (Banerjee et al. 2017). For example, multiple pathways (NF-κB, Nrf2, and SIRT1— sirtuin 1) were found to be closely associated with oxidative stress and miRNA (Kura et al. 2020) (Fig. 8).

Fig. 8

Under oxidative stress, miRNAs affected different signaling mechanisms such as Nrf2, NF-κB, and SIRT1. ROS inhibits or induces the level of miRNA expression and subsequent their target genes regulation. The upper arrow reflects elevated oxidative stress/signaling pathway stimulation. Nrf2: nuclear factor erythroid 2; NF- κB: nuclear factor kappa-light chain- enhancer of activated B; SIRT1: sirtuin 1

miRNA could be a promising new approach in prognostic assessment, clinical diagnosis as well as oxidative-stress-related CVD therapy intervention. Understanding the crosstalk between miRNAs, ROS, and cardiovascular diseases that lead to new therapeutic approaches focused on suppressing the effects of ROS, with the potential for improvement or prevention of CVDs progression (Kura et al. 2020). Future miRNA studies may take advantage of numerous recent technological advances. High-throughput functional screening of miRNAs has increased the speed and accuracy of the discovery of new miRNAs associated with diseases (Fiedler et al. 2014). In vivo targeted delivery of miRNA is another technological advance predicted to move the field forward in the development of different animal models for studying miRNAs as well as enhancing the clinical translatability of pre-clinical studies (Kwekkeboom et al. 2014).

Biomarkers of inflammatory processes

NF-κB launches and boosts the inflammatory process via transcriptional activation of cellular adhesion molecules, cytokines, and chemokines (Brigelius-Flohé and Flohé 2011). This important pathological process plays a crucial role in the pathogenesis of several acute and chronic inflammation-related diseases for instance sepsis, asthma, and CVD (Oni-Orisan et al. 2013).

Regarding cardiovascular function and inflammation, it has been found that the expression of pro-inflammatory markers and cytokines (such as NF-κB, IL-1, IL-6, TNF-α, lymphotoxin, and interferon-γ (IFN-γ)) increased in vascular injury. Besides, C- reactive protein (CRP) which is an acute-phase protein is produced from the liver in response to tissue injury, inflammation, and infection (Brigelius-Flohé and Flohé 2011), and can act as a systemic inflammation biomarker (Goldstein et al. 2011). In atherosclerosis, C-reactive protein (CRP) is correlated with serum UA levels (Mazidi et al. 2018). Experimentally, it has been found that UA increases the release of chemokine monocyte chemoattractant protein-1 and IL-1β, IL-6, and TNF-α synthesis. Also, UA might contribute to atherosclerosis and the progression of human vascular disease through a pro-inflammatory pathway (Lyngdoh et al. 2011).

In the metabolic regulation of CRP, IL-6 is involved where chronic inflammation increases the levels of inflammation markers which result in high liver CRP in response to IL-6, which mediates a vasodilation reduction and vascular damage increase (Teixeira et al. 2014). Subsequently, NO production is decreased by high levels of serum IL-6, and CRP via suppressing eNOS and facilitating thrombi formation (Teixeira et al. 2014). IL-1β, IL-6, and TNF-α have also been found to be elevated in metabolic syndrome subjects (Koçak et al. 2016). Therefore, cytokines are useful biomarkers or targets for atherosclerosis therapy as they are increasing their pathogenicity. This could be due to their involvement in pro-inflammatory and pro-angiogenic responses (Zhao 2018).

Also, fibrinogen has been recognized as a marker of thrombosis as well as inflammation and was associated with increased CVD risk (Sabater-Lleal et al. 2013). Eicosanoids are biologically active fatty acids derived through oxidative metabolism of arachidonic acid by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 enzyme systems (Mozaffarian and Wu 2011). COX is known to induce the conversion of the arachidonic acid into hydroperoxy-endoperoxide, prostaglandin G2, which is reduced to the precursor for eicosanoid synthesis called hydroxyl-endoperoxide prostaglandin H2 (Yamaguchi and Fukasawa 2021). The expression of COX2 and eicosanoids production, especially in macrophages and foam cells, is augmented in atherosclerotic lesions (Ricciotti and FitzGerald 2011). Also, COX-derived prostaglandins and biosynthesis of prostaglandins are important regulators of inflammation, so the inhibition of this reaction is considered as potent anti-inflammatory effects in preclinical models and humans (Ricciotti and FitzGerald 2011). Also, it has been shown that the metabolism of arachidonic acid to pro-inflammatory leukotrienes is catalyzed by the LOX pathway. Pro-inflammatory leukotrienes are known to induce vasoconstriction and elevate atherosclerosis risk (Katkam et al. 2019b). It was observed that ALOX5 knockout induced resistance against atherosclerosis progress in animal models (Sugamura and Keaney Jr 2011). In advanced plaques, ALOX5 levels were increased (Bhattacharyya et al. 2014). Most notably, prostaglandin E2 and thromboxane A2 are key pro-inflammatory products of this pathway that activate NF-κB, promote leukocyte infiltration into the tissue, and thus drive the vascular inflammatory response (Brooks et al. 2018).

Physiological tests for CVD prediction

The mechanisms of cardiovascular system multiphysics mechanisms can be detected by cardiac physiological tests. One of these tests is blood pressure which reflects the artery's hemodynamics. High blood pressure causes atherosclerosis development and it is common in strokes or heart attacks (Daugherty et al. 2017). Also, for screening vulnerable myocardium resulting in acute MI, an electrocardiogram (ECG) has been used as it assesses the heart electrophysiology and its abnormalities (Stone et al. 2011). Furthermore, arterial stiffness measurement by pulse wave analysis or aortic pulse wave velocity indicates the arteries’ blood fluid flow and the arterial wall hardening degree (Members et al. 2010) which consequently leads to arteriosclerosis. Another test is the index for ankle-brachial blood pressure which is the ratio between ankle and arm systolic pressure and assessed blood vessel structure and function as well as peripheral vascular disease. Measuring. IMT is another marker of early atherosclerosis and predicts CVD progress (Libby et al. 2011).

Omics technologies to assess oxidative stress and inflammation: promises and difficulties to overcome

The omics technologies show changes in the disease-related DNA, RNA, epigenetics, proteins, and metabolism. When oxidative stress is known to contribute to the development of a disease, genomic markers could be provided for this imbalance by the identification of specific disease mutations (Lowe 2014). The process of biomarker discovery can be considerably accelerated via omics technology, particularly by the combining of genomics, transcriptomics, proteomics, and metabolomics in a multi-omics strategy (Lee et al. 2018). In the next part, we will review the main components of the cellular redox response system utilizing “omics.”

Redox transcriptome

In response to oxidant stress, mammalian cells induced signaling cascades which can trigger the expression of a broad range of protein-coding genes that control the cellular redox status (Ma 2010). Noncoding RNAs contribute to redox gene expression regulation as well as protein-coding genes (Giannakakis et al. 2015). Genome-wide transcriptional profiling may also help predict oxidative stress biomarkers or related illnesses (Wang et al. 2018a). The findings of Genome-Wide Association Study (GWAS) on risk loci in a wide cohort of the population indicate a significant impact of arterial wall-specific inflammatory pathways in the CAD development and progression; for example, SNPs in or near genes associated with cellular adhesion, leukocyte migration and atherosclerosis (platelet endothelial cell adhesion molecule-1, rs1867624), and coagulation and inflammation (endothelial protein C receptor, rs867186 (p.Ser219Gly) were recognized (Howson et al. 2017). Also, certain GWAS data included several risk loci that are associated with cardiovascular inflammation (Klarin et al. 2017).

Furthermore, chromatin immunoprecipitation (ChIP)-Seq combines ChIP with massively parallel DNA sequencing and can integrate detection of genome-wide protein–DNA binding events (transcription factor-gene interaction) with chemical modifications of histone proteins (Furey 2012). Utilizing a combination of ChIP-Seq and microarray analyses provides a valuable method to identify upstream regulatory factors that control gene transcription. Through this approach, novel targets of the Nrf2 antioxidant transcription factor have been identified, providing a picture of a global transcriptional network regulated by Nrf2 (Chorley et al. 2012).

Redox proteomics

It is a branch of proteomics that aims at detecting oxidized proteins and quantifying the status of oxidative changes in the proteomes of interest. Such quantitative information is important for the building of mathematical models to decode the dynamics of redox associated with biochemical pathways and networks. In this regard, there have been studies focusing on the development of proteomics techniques to identify all redox-regulated proteins and redox-active compounds and to elucidate redox control networks in cellular systems (Buettner et al. 2013).

Fedorova and colleagues carried out a successful study using large-scale omics data in redox biology by applying a multi-omics approach to classify crosstalk signaling between lipid and protein carbonylation in rat cardiomyocytes by using the dynamic nitrosative stress model (Griesser et al. 2017). Lipidomics and proteomics system biological integration allowed over 167 unique proteins to be identified with 332 sites altered via reactive lipid peroxidation products. Although redox proteomics is still in its early stages, mass spectrometry (MS) driven biomarkers are a promising strategy in diseases related to oxidative and nitrosative stress. Redox proteomics is becoming a key tool for new insights into several disease-related protein modifications. Clinical research by recognizing new drug targets and diagnostic markers can benefit from redox proteomics (Wang et al. 2018a).

Redox metabolome

Metabolomics is one of the most groundbreaking medical technologies and is also known as metabonomics. By chemical analysis of a wide variety of biological sample metabolites, such as urine and blood, offers a direct functional read-out of phenotypes. Metabolites (< 1500 Da) reflect the cellular metabolism output, account for the activity and expression of genes, transcripts, and proteins, and offer unique insights into small molecule regulation, which may reveal new biochemical patterns. The redox metabolome is a metabolome redox-active subset. Redox and nitrosative (RN) reactions play a major role in CVD development and progression. The homeostatic regulation of a wide range of cellular and organ functions usually includes RN reactions. Conversely, allostasis which can cause CVD may result from the imbalance of these reactions (Deidda et al. 2018).

Nuclear magnetic resonance (NMR) and liquid chromatography (LC) or gas chromatography, combined with MS, are two main analytical methods for global metabolomic profiling. They can be applied to measure the composition and concentration of both specific and non-target metabolites in disease diagnosis and biochemical pathways analysis. The redox metabolic profiling techniques can be used to recognize metabolic biomarkers and to detect redox-regulated signaling mechanisms (Wang et al. 2018a).

DNA methylation analysis

DNA methylation takes place through the covalent addition of a methyl group at the five’ carbon of the cytosine ring, which forms 5-methylcytosine. The mammalian gene promoter regions which regulate the associated gene expression usually have cytosine–guanine-rich regions (CpG islands) in their genetic sequence. Methylation at specific sites can prevent the binding of transcriptional machinery or ubiquitous transcription factors to regulatory sites on the DNA double helix (Stone et al. 2011). The subsequent alteration in chromatin structure renders the promoter sequence of the target DNA inaccessible to activating transcription factors and inhibits gene expression.

Methylation controls gene activity, but without histone deacetylation and chromatin-binding proteins, it is not enough to repress the gene activity. The subsequent regulation of gene expression may lead to various disease processes involving oxidative stress (Giannakakis et al. 2015). Moreover, eicosapentaenoic acid allows a systematic evaluation of numerous CpG sites across the genome concerning the phenotype or disease of interest (Soler-Botija et al. 2019). The prediction of different drug responses can be assisted by epigenetic knowledge. Particularly in the scientific community, epigenetic biomarkers become identified as tools for the diagnosis and prognosis of CVDs (Soler-Botija et al. 2019).

While omics technologies have a wide range of applications in various fields, current challenges and technique limitations are present. The sensitivity and resolution of omics instruments have constantly been an issue in the field. For instance, only highly abundant proteins can be detected by some proteomics techniques due to insufficient sensitivity for low abundance proteins. Also, measurement and monitoring of the redox proteome have not achieved high resolution. Also, RNA-Seq examines mRNA sequence data from individual cells and performs accurate quantitative transcriptome measurements with greater cellular differentiation resolution than currently proteomic methods. Also, given the heterogeneity of responses across various cells, new techniques are needed to revise the redox transcriptome (Wang et al. 2018a).

Regarding proteomics and metabolomics studies, sample preparation often eliminates the ability to detect differences in protein or metabolite levels within several subcellular compartments. To overcome this hurdle, attempts have focused on subcellular fractionation of samples before analysis by using differential centrifugation (Drissi et al. 2013). Chen et al. also reported an immunoprecipitation method for isolation of intact mitochondria rapidly for metabolomics analyses (Chen et al. 2016a). As instrument sensitivity continues to improve, single-cell and subcellular analyses will become more feasible.

Nevertheless, advances in innovative omics technologies have contributed to success in generating the redox transcriptome, proteome, and metabolome as well as rapid accumulation of large-scale data. The global study of redox biology needs to combine these heterogeneous or broad omics data to better understand the mechanism of redox metabolism and its consequences for human diseases (Wang et al. 2018a). The limitation of metabolomic techniques is that they do not recognize directly ROS and NO; however, certain molecules such as succinate, oxidized glutathione, and urea cycle intermediates involved in RN reactions can be measured and analyzed, thus allowing an indirect examination of these pathways (Deidda et al. 2018).

Besides, information about identified metabolites’ biochemical pathways and biological function, both in physiological and pathological conditions, is essential for the proper understanding of the findings resulting from metabolomics application to the investigation of ROS and NO metabolism and signaling (Deidda et al. 2018).

Management of CVDs

For CVDs prevention and treatment, a healthy lifestyle is highly recommended because it is safe and cheap (Fyhrquist et al. 2013). This lifestyle includes ideal calorie intake, both good nutrition and psychological status as well as avoiding smoking (Fontana 2018).

Nutritional modulation by calorie restriction for the management of obesity and CVD

Calorie restriction (CR) has useful impacts on cardiovascular health by mechanisms including suppression of chronic inflammation and dyslipidemia as well as stimulation of immune response caused by increased cytokine, adipokine production (Meydani et al. 2016). Sirtuins a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases (HDACs) (Singh et al. 2017) mainly Sirt1 controls various aspects of the caloric restriction (CR) response including insulin secretion, glucose homeostasis, fat metabolism, physical activity, and stress resistance (Guarente 2013). Stimulation of Sirt1 confers anti-oxidative and anti-inflammatory effects in the vasculature, causing attenuated vascular senescence (Kida and Goligorsky 2016). Besides, Sirt1 plays a significant role in the cardiac adaptive response to various stresses, such as oxidative stress, I/R, and starvation (Hsu et al. 2010; Akkafa et al. 2015). Besides, cardiac Sirt1 mediates the cardioprotective effect of CR by suppressing local complement system activation after I/R (Yamamoto et al. 2016). CR primes cardiac mitochondria into a stress-resistant state, leading to improvements in myocardial ischemic tolerance. Based on the finding that enhanced sirtuin activity was associated with a decline in the amount of acetylated mitochondrial proteins in the CR heart, in this regard, the beneficial effect of CR on mitochondrial function is mediated by deacetylating specific mitochondrial proteins. Among numerous CR-induced deacetylated proteins, for example, the deacetylation of NDUFS1 (complex I) and/or Rieske subunit of cytochrome bc1 complex (complex III) plays a key role in the reduced ROS production in the mitochondria during early reperfusion. Low-dose resveratrol (RSV), a natural bioactive polyphenolic compound present in a wide variety of foods, particularly red grapes (Lee et al. 2014) also caused a lower ROS development and improved cell survival in cultivated neonatal cardiomyocytes following hypoxia/reoxygenation without raising expression levels of MnSOD in a sirtuin-based way (Shinmura et al. 2011). Additionally, CR inhibits insulin resistance (Ruggenenti et al. 2017); decreased oxidative damage for protein, lipid, and DNA leading to boosting endothelial function (Il’yasova et al. 2018).

A poor diet, rich in refined and preserved food as well as an imbalance of sleep and exercise, has resulted in an epidemic of obesity in the sedentary lifestyle. Individuals with a 30 or higher index of body mass are overweight and obese (Most et al. 2017). Obesity is a risk factor for many CVDs such as MI, hypertension, and atherosclerosis (Halade and Kain 2017). Obesity induces cardiovascular disease via ectopic lipid deposition, an increase of blood glucose level, and the development of a procoagulant state (Flegal et al. 2010). Obesity has been found to induce pro-inflammatory adipokines expression and diminished anti-inflammatory adipokines expressions such as TNFα and IL-6, developing a chronic, low-grade inflammatory condition (Flegal et al. 2012). Also, under obesity conditions, adipokines were shown to stimulate both metabolic diseases and CVDs (Ouchi et al. 2011).

Also, metabolic disease has been linked strongly with low-level inflammation. For instance, an adipose mass increase in women suffering from obesity is associated with an elevation in pro-inflammatory marker CRP levels in the serum (Zeng et al. 2021). Conversely, weight loss decreased serum IL-6 and CRP and levels (Meghatria and Belhamiti 2021). These results strongly demonstrated that an obesity-linked inflammatory state is due to changes in the expression of adipocytes cytokines (Samaras et al. 2010). For example, in obesity and diabetes models, adipose tissue TNFα expression is induced (Nakamura et al. 2014) and in the case of weight loss in obese people, there is a decline in the levels of TNFα (Ouchi et al. 2011).

Dietary/supplemental antioxidant and drugs with antioxidant/anti-inflammatory properties

As described before, there is a balance between the formation of ROS / free radical and endogenous antioxidant defense mechanisms in normal and healthy body conditions. If this balance is disrupted, it can lead to oxidative stress and damage to all essential cellular components such as DNA, proteins, and membrane lipids leading to cell death (Senoner and Dichtl 2019). Consequently, it can cause numerous diseases such as CVDs and inflammation (Arulselvan et al. 2016).

The cardioprotective effects could include antioxidation, anti-inflammation, antiplatelet, blood pressure reduction, lipid metabolism modification, blood glucose regulation, endothelial function improvement, and myocardial damage mitigation. Besides, the mechanisms of action could include the modulation of related enzyme activity, gene expression, and signaling pathways, as well as some other CVD-related biomarkers (Tang et al. 2017).

Phenolics and flavonoids contents are contributed to the antioxidant activity of natural ingredients. Also, trace metals such as Cu, Zn, Mg, Mn, and Se have been reported to perform significant functions in the antioxidant system (Ravipati et al. 2012). The use of naturally occurring antioxidants (Fig. 9) and the development of chemical antioxidants to reduce or prevent CVD are of importance over time, given the prevalence of CVD and the role of ROS in many cardiovascular pathologies, as stated above.

Fig. 9

Dietary and supplementary antioxidants for decreasing cardiovascular risk

Phenolics and flavonoids have been considered anti-inflammatory compounds in addition to their antioxidant activity. The results of anti-inflammatory research for natural extracts and their active ingredients compounds proved by hindering both MAPK and NF- κB pathways, which function to produce numerous mediators for proinflammation (Arulselvan et al. 2016). Polyphenols may be classified into natural, semi-synthetic, and synthetic compounds, and have been known to minimize the risk of MI, stroke, and cardiovascular death (Peterson et al. 2012).

Studies have demonstrated that the intake of polyphenols can prevent CVD onset due to their antioxidant and antiatherosclerotic activity (Rizzi et al. 2016). It was found that grape polyphenols supplementation significantly decreased the serum TMAO level which is considered an emerging risk factor for CVD (Annunziata et al. 2019a, b). The individual response to polyphenols intake has been attributed to the PON1 enzyme gene which encodes for glycoprotein that is known to protect lipoproteins from oxidation and consequently strongly associated with HDL antioxidant and anti-inflammatory activity (Barrea et al. 2020).

Besides, RSV provides several benefits for health, including antioxidant activity, through increased antioxidant enzyme activities and free-radical scavenging (AlBasher et al. 2020). RSV also has many biological characteristics, such as anti-tumor, anti-inflammatory, anti-aging, anti-hyperlipidemic, cardioprotective as well as neuroprotective effects (Benayahoum et al. 2013). It was found that RSV stimulates a dose-dependent elevation in the activity of the NAD⁺ synthetic enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT1) leading to increased NAD⁺ levels enhancing SIRT1 activity which used NAD⁺ as a substrate to induce its gene-silencing activity (Grant 2010). SIRT1 has been shown to deacetylate and activate eNOS (Guo et al. 2020), and after arterial injury, whole body or smooth muscle cell-specific overexpression of SIRT1 protected mice against neointimal hyperplasia (Li et al. 2011; Bae et al. 2013).

Extra virgin olive oil (EVOO) is rich in polyphenols. When comparing EVOO foods with corn oil meals, healthy individuals with EVOO intake show a considerable decrease in oxidative stress levels and markers of endothelial dysfunction because of the high polyphenolic contents of olive oil (Carnevale et al. 2014). Also, dark chocolate suppresses platelet function only in smokers by reducing oxidative stress; this effect appears to depend on its polyphenolic content (Carnevale et al. 2012). The distinct composition of nuts, which includes complex carbohydrates, unsaturated fats, protein, vitamins or fiber, minerals except for sodium, plant sterols, and other bioactive components, as polyphenols, makes nuts special among plant foods (Ros 2010). A reduced CVDs risk, as well as obesity, cancer, and diabetes mellitus, was associated with regular intake of nuts (Aune et al. 2016).

Besides, tea polyphenols, also known as catechins, were found to increase SOD and CAT activities, stimulate the free radicals scavenging, and decreased lipid peroxide formation. Also, they are involved in inducing apoptosis of VSMCs by upregulation of p21, p53, and NF-κB, thus decreasing the risk of atherosclerosis development (Chen et al. 2016b). In a systematic review to analyze the flavonoid’s impact on vascular function (Kay et al. 2012), it was found that they improved blood pressure and both acute and chronic flow-mediated dilation (FMD). Anthocyanins, a type of flavonoid with significant antioxidant effects and positively affect the vascular endothelium function (Heiss et al. 2010). Anthocyanin supplementation improved both acute and chronic FMD are improved with no improvement in the reactive hyperemia index.

It is well evident that both anthocyanins and polyphenols can prevent the onset of CVD (Du et al. 2016), due to their antiatherosclerotic and antioxidant and effects (Wallace et al. 2016). There is a very low bioavailability for phenolic compounds where only 10% of them are absorbed in the small intestine, whereas about 90% is excreted or metabolized by the intestinal microbiota (Kawabata et al. 2019). Therefore, the primary protective effect of anthocyanins cannot be due to the antioxidant properties, which will be active only at the intestinal level, but to their action as secondary intracellular mediators in different signaling pathways. Other studies highlighted the cardioprotective and anti-inflammatory effects of anthocyanins showed also anti-inflammatory and cardioprotective effects. In this regard, the intake of anthocyanins promotes NO production that improves blood circulation and, on the other hand, can inhibit Nf -kB transcription, reducing pro-inflammatory molecule production (Kruger et al. 2014). Also, in a randomized controlled clinical trial (RCT) to study the anti-inflammatory impact of anthocyanins (Zhu et al. 2013), a total of 150 subjects with hypercholesterolemia consumed a purified anthocyanins mixture (320 mg/day) or a placebo twice a day for 24 weeks. The intake of anthocyanins significantly diminished the levels of plasma IL-1β, serum CRP, soluble vascular cell adhesion molecule-1 compared with the placebo as well as a significant difference in the HDL and LDL-cholesterol levels between the two groups (Zhu et al. 2013).

Quercetin, a dietary antioxidant flavonoid, has a therapeutic and protective impact on lipopolysaccharide (LPS)-induced oxidative stress and vascular dysfunction in mice study (Kukongviriyapan et al. 2012). Quercetin improved the eNOS expression in the aortic tissues and reduced the levels of nitrate/nitrite while abolished the iNOS expression compared to the LPS injected mice. Also, it suppressed LPS increased aortic O₂^•− production and markedly reduced protein oxidation and lipid peroxidation as well as restored the GSH redox ratio. Moreover, in a hypercholesterolemia animal model study, quercetin showed a significant decrease in hepatic thiobarbituric acid reactive substances (TBARS) level and plasma levels of total lipids, whereas it markedly increased liver CAT activity and total thiol level as compared with control rats (Khamis et al. 2017).

In a previous study of our research group, it was found that hesperidin, a citrus fruit bioflavonoid, can protect against cardiomyopathy caused by doxorubicin via suppressing oxidative stress, inflammation, and apoptosis (Donia et al. 2018). The findings of a prospective study to assess the relationship between flavonoid consumption and cardiovascular death (McCullough et al. 2012), it was showed that study participants with the highest quintile total flavonoid intakes lowered the cardiovascular risk by 18%, regardless of the adjustment of many cardiovascular risk factors.

Oxidative stress is inversely correlated with the Mediterranean diet adherence, primarily because of the decrease of GSSG concentrations, even following to modification of different risk factors for CV (Duda-Chodak et al. 2015). Omega-3 or omega-6 polyunsaturated fatty acids have been found to minimize the occurrence of CVDs due to their anti-atherogenic, anti-thrombotic effects as well as their lowering effects on blood pressure (Sokoła-Wysoczańska et al. 2018). Eicosapentaenoic acid and docosahexaenoic acid, two n-3 polyunsaturated fatty acids, reduced inflammation, and boost endothelial function, thus inhibiting atherosclerosis development (Bhatt et al. 2019). They diminished endothelial DNA damage by ROS (Sakai et al. 2017). Also, their modified lipid effectors, namely resolvins, maresins, and protectins, have anti-inflammatory effects (Sies et al. 2017).

It was found that vitamin C is promising in studies with 10–55 participants to evaluate the impact of vitamin C in CHF (Daiber et al. 2017). Also, higher vitamin E intake in women and men lowers the coronary disease risk (Fihn et al. 2012). Many studies showed that vitamins C, E, and other antioxidants can decrease CVD by trapping organic free radicals and inhibiting excited oxygen molecules to prevent tissue damage (Lobo et al. 2010). Antioxidants may be able to slow or prevent atherosclerotic plaque formation, likely, by inhibiting the oxidation of LDL-cholesterol (Nordestgaard and Varbo 2014). However, the results of studies concerning the role of vitamin C and E in human CVD prevention are still controversial. Vitamin C supplements, exceeding 700 mg/day, were significantly linked to 25% decreases in coronary heart disease risk in a pooled analysis of nine cohorts (Widmer et al. 2015).

In RCT including 4641 middle-aged men to assess whether the long-term supplementation of vitamin E or vitamin C can decrease the risk of major cardiovascular events, it was indicated that either vitamin E or vitamin C cannot reduce the risk of major cardiovascular events by following 8 years (Zhu et al. 2021). Another RCT reported a possible anti-inflammatory effect of 500 mg of vitamin C twice a day in 64 people with obesity, hypertension, and/or diabetes. In this study, vitamin C might act by the induction of the decline in CRP, IL-6, and fasting blood glucose after 8 weeks of treatment might be induced by vitamin C (Ellulu et al. 2015).

Also, the intake of antioxidant vitamins (vitamin A, C, and E) from food and supplements in over 3000 postmenopausal women with no CVD was tested for a period of 7-years follow-up, indicating that the vitamin E intake from food was inversely associated with the death risk from coronary heart disease (Sugamura and Keaney Jr 2011).

The thiol-containing antioxidant N-acetylcysteine (NAC) can regenerate the intracellular antioxidant reservoirs, as NAC deacetylation produces cysteine, which is a precursor for GSH. Initial small trials evaluating the intravenous NAC efficacy on acute MI and ischemic heart disease were shown to be promising in infarct size limitation (Samuni et al. 2013).

Furthermore, probiotics use can enhance cardiovascular function and have beneficial effects on patients with heart failure (Vasquez et al. 2019). The regular intake of probiotics such as kefir which maintains the bowel balance could have partial cardiovascular benefits depending on reducing oxidative stress (Vasquez et al. 2019). Kefir has been found to protect from vascular dysfunction of the endothelium and incorrect impaired autonomic cardiovascular function (Silva-Cutini et al. 2019), including inhibition of the angiotensin-converting enzyme (Brasil et al. 2018). Probiotics may thus be a promising natural contributor to the prevention/therapy of CVD, including hypertension (Vasquez et al. 2019).

In a pilot study to address the probiotics prognostic effects in patients with heart failure class II or III and left ventricular ejection fraction, < 50% were randomized to probiotic therapy with Saccharomyces boulardii or placebo for 3 months in a double-blinded fashion (Costanza et al. 2015). The left atrial diameter, as well as the levels of CRP, UA, and creatinine, was reduced considerably in patients treated with probiotics. Therapy using probiotics was also safe and well-tolerated without reporting adverse consequences or negative events (Vasquez et al. 2019). More mechanistic studies are therefore required to identify the missing links to the safety of fermented foods, such as pre-, pro-and synbiotics, and of the bioactive compounds of fermented foods on blood pressure neural control (Vasquez et al. 2019).

Due to the limitation of the common antioxidants in attenuating heart disease and the strong animal models studies that promoted the concept that limiting mitochondrial ROS production or improved ROS mitochondrial scavenging can be extremely useful for the heart, thus there has been considerable effort to identify mitochondria-targeted antioxidants as drugs. MitoTEMPO, SS-31/MPT-131, and mitoquinone (mitoQ) have been reported a positive effect as mitochondria-targeted agents (Peoples et al. 2019). Mito TEMPO is a mitochondria-targeted agent mimicking SOD and composed by conjugating nitroxide of piperidine to the lipophilic triphenylphosphonium cation (TPP⁺), where the accumulation of it in the matrix depending on the membrane potential (Leopold 2015). It causes superoxide detoxification to restrict the formation of hydroxyl radicals via cycling between its oxoammonium and nitroxide forms, as well as ferrous iron oxidation (Zielonka et al. 2017). In an animal study, mitoTEMPO efficiently decreased the ROS production in both cytosolic and mitochondrial compartments in case of myocytes failure, and repeated administration could prevent heart failure (Dey et al. 2018).

The antioxidant MitoQ has been documented to reduce oxidative stress and increase the antioxidant GPX1, which catalyzes the conversion of peroxides into alcohol and water (Escribano-Lopez et al. 2016). Also, to modulate the leukocyte-endothelium interaction (Escribano-Lopez et al. 2016). The cardioprotective effect of MitoQ involves raising leucocyte velocity and reducing its flux and adhesion to the endothelium, thus limiting inflammation as well as oxidative stress (Escribano-Lopez et al. 2016). MitoQ is targeting ubiquinone attached to the TPP⁺ cation in the mitochondrial matrix. On targeting the matrix, ubiquinone is reduced to ubiquinol, which acts as a carrier for electrons to boost the complexes I / II electron transfer to complex III (Dryhurst 2012), and as well as it acts as an antioxidant by reducing the peroxidation of lipids (Victor et al. 2011).

In in vitro studies, mitoQ was found to significantly cause decreased oxidative damage and stimulated the protection against cell death which is induced H₂O₂ as well as chemically induced cardiac I/R injury (Bayeva et al. 2013). In in vivo IR injury Langendorff isolated heart model, it has been shown that mitoQ administration in drinking water to rats decreased cytochrome c release, mitochondrial damage, caspase 3 activations, and death of cardiomyocyte (Espinosa-Diez et al. 2015). This decrease in cardiomyocyte loss has been found to strongly link to high cardiac contractility and preserved mitochondrial function of the respiratory chain, so mitoQ has both mitoprotective and cardioprotective effects (Espinosa-Diez et al. 2015). It also maintained respiratory chain function and mitochondrial membrane potential as well as reduced the oxidant sensitivity which induced mitochondrial-permeability transition pore (Junior et al. 2018).

SS-31 which is D-Arg-2′6′-dimethylTyr-Lys-Phe-NH2 and its acetate salt MTP-131 (also called Elamipretide or Bendavia) are peptides with antioxidant activity, high membrane permeability, as well as solubility and, could target the mitochondria (Szeto 2014). Its accumulation at the inner mitochondrial membrane is independent of membrane potential, it could thus act on both healthy and diseased mitochondria. Specifically, SS-31 could bind to inner membrane phospholipid called cardiolipin, and regulates mtDNA nucleoid distribution, cristae architecture, respiratory chain complex integrity, and supercomplex organization (Rochette et al. 2014). Also, SS-31 modulates the interaction of cardiolipin with cytochrome-c specifically (Birk et al. 2013). The balance between the electron carrier and cytochrome-c peroxidase activities was shown to be regulated by cardiolipin to mediate oxidative mitochondrial damage. This balance is mediated through hydrophobic binding between cytochrome c and cardiolipin results in partial cytochrome c unfolding that boosts the activity of its peroxidase. SS-31 binds to cardiolipin and disrupting its interaction with cytochrome c, thus inducing the cytochrome c action as a respiratory chain electron carrier (Hanske et al. 2012).

Carvedilol functions as a mitochondrial complex-I inhibitor that is active in the cardiotoxicity-induced anthracycline mechanisms (Montezano and Touyz 2014). It also reduced the harmful effect of doxorubicin on the left ventricular ejection fraction and induced lipoperoxidation in vivo models (Carvalho et al. 2014).

Besides, the antioxidant composition may differ in patients, and before treatment, predicting antioxidant profiles can be useful in selecting the candidate for antioxidant therapy and avoiding over exposition. Also, monitoring of the antioxidant status of patients will allow the selection of subjects who may benefit from vitamin supplementation before and during therapy (Vardi et al. 2013). The correlation between patients’ vitamin lack and disease symptoms is suggested primarily by consuming oxidation-sensitive vitamins associated with inflammation, leading to a variety of secondary effects (Mangge et al. 2015).

CKD is associated with mitochondrial dysfunction. The common complication of CKD is iron deficiency anemia that is associated with poor clinical outcomes that affect the function of mitochondria and intensify oxidative stress (Nuhu et al. 2019). The increased risk of ROS development in iron deficiency anemia in CKD leading to increased RBC death, anemia, and oxidative stress severity (Rysz et al. 2020). It has been found that iron deficiency anemia, oxidative stress is partly mediated via antioxidant reduction (Prats et al. 2014) and timely replacement of iron (via intravenous route rather than oral) and antioxidant therapies could lead to clinical improvement. In this regard, iron therapy improved iron deficiency anemia in CKD without a significant impact on renal function or oxidant status (Nuhu et al. 2019).

In the treatment of patients with a proven atherosclerotic disease with highly specific anti-inflammatory therapies (for instance cytokines targeted monoclonal antibodies), there was a decreased cardiovascular mortality. Current antidiabetic cardiovascular drugs (e.g., sodium-glucose transport protein 2 (SGLT2) inhibitors, Dipeptidyl Peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1(GLP-1) analogs) inhibit inflammatory and detrimental redox mechanisms and therefore decrease the CVDs risk (Steven et al. 2019).

Anti-inflammatory mechanisms for SGLT2 can include weight loss and reductions of ketone and UA as well as inflammation of the adipose tissue, or oxidation stress attenuation (Bonnet and Scheen 2018). It was found that therapy of obesity, hyperlipidemia, hyperglycemia, and oxidative stress, as well as various mice inflammation parameters with type 1 or 2 diabetes mellitus, were improved by SGLT2 inhibitor ipragliflozin (Tahara et al. 2014). Additionally, the SGLT2 inhibitor dapagliflozin ameliorated nephropathy and glucose homeostasis and decreased inflammation markers in the genetically diabetic model called db/db mice (Terami et al. 2014). Many SGLT2 inhibitors including luseogliflozin, empagliflozin, and dapagliflozin have anti-inflammatory effects in the progression of atherosclerosis (Han et al. 2017). Moreover, Shin et al. showed that dapagliflozin decreased oxidative stress by restoring Mn-SOD, Cu/Zn SOD, and CAT expression in renal tissues of diabetic animals (Shin et al. 2016).

In this regard, SGLT2 inhibitor TA-1887 inhibits oxidative damage by increasing CAT and Mn-SOD expression (Sugizaki et al. 2017). The empagliflozin has been reported to reduce free-radical production and improve oxidative stress-induced vascular dysfunction in the aortic vessels of diabetic rats via mitochondrial function recovery while suppressing pro-oxidant agent activity (Oelze et al. 2014). The cardiovascular safety profiles empagliflozin and canagliflozin were studied in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose and Canagliflozin Cardiovascular Assessment Study trials, respectively (Rastogi and Bhansali 2017). Both studies indicated the use of SGLT2 inhibitors was beneficial and decreased cardiovascular deaths, as well as decreased incidence of MI and stroke (Neal et al. 2017). Given the antioxidant effects of the SGLT2 inhibitors detailed above, it is perhaps interesting to infer that this antioxidant effect may have contributed toward the reduction in cardiovascular events observed in the previously mentioned trials (Yaribeygi et al. 2019).

Statins have been found to significantly decrease the risk of key cardiovascular events (Collaboration 2012). They decreased the levels of proinflammatory chemokines and cytokines, adhesion molecules such as NF-κB and P-selectin, and monocyte activation. They also minimize oxidative stress via decreasing NOX and O₂^−. production as well as oxidation of LDL and by rising free radical scavenging. Moreover, statins increase eNOS activity and NO levels via increased BH4 bioavailability in patients with CAD (Antoniades et al. 2011).

Also, statins serve as inhibitors of 3-hydroxy-3 methylglutaryl- coenzyme A and suggested to minimize the risk of coronary heart disease due to their lipid reduction effects (Dagli et al. 2010). Colchicine has also been used as an adjuvant to atherosclerosis treatment based on its anti-inflammatory effects. Thereby decreasing the production of monocyte proinflammatory cytokines such as IL-1β and IL-18 as well as inhibiting the functioning and activation of neutrophils (Martínez et al. 2018).

To prevent cardiovascular events in CKD patients, ideally targeted intervention goals should include control of blood pressure, lipid, diabetes, proteinuria reduction, anemia treatment, management of metabolic abnormalities, and lifestyle changes including smoking cessation, low salt consumption, achieving a normal body mass index. The use of β blockers, renin-angiotensin blockers, diuretics, statins, and aspirin is helpful in the early stages of CKD (Liu et al. 2014).

Exercise training and hormesis as an adaptive response to oxidative stress

Physical activity and exercise, both aerobic and anaerobic, lead to the prevention of CVD (Kokkinos and Myers 2010). Consequently, maximal levels of exercise capacity are known to suppress cardiovascular mortality and morbidity. On the other hand, acute exercise stimulates the ROS overproduction leading to an imbalance between free radical production and the antioxidant defense causing oxidative stress (Dekleva et al. 2012). It was known that physical inactivity and decrease aerobic capacity are independent and potent for CVD mortality prediction. However, an increase in physical exercise levels cannot decline the higher mortality risk in case of extensive adiposity (Berrington de Gonzalez et al. 2010). Ideally, regular exercise practice has a significant impact on optimizing cardiovascular and metabolic health and can protect against obesity by elevating the biogenesis of mitochondria as well as the consumption of calories and oxygen (Holloszy 2011). Also, it upregulates glucose transporter type 4 as well as glycogen synthase leading to insulin responsiveness in muscle (Soufi et al. 2014). In the case of obesity-associated with hypertension, regular exercise upregulates the skeletal muscle lipoprotein lipase lead to an optimal lipid profile (Richter and Hargreaves 2013), and a decrease in blood pressure level (Bouchard et al. 2011).

Besides, the important role of endurance exercise to protect against endothelial dysfunction and arterial stiffening is mediated via its significant antioxidative stress and anti-inflammatory effects. For example, the wheel running in the animal study increases NO bioavailability, this may be due to an increase in shear stress which raises the AKT1 expression and subsequent phosphorylation eNOS. Consequently, it decreased the rate of accumulation of nitrotyrosine as well as the end products of advanced glycation, and the decrease in NOX expression in the vasculature as well as NF- κB leading to a decrease in serum cytokines concentration (Seals et al. 2014). Besides, in calorie restriction for induction of weight loss via anaerobic or isometric resistance training, fat loss and basal metabolic rate were found to be induced resulting in boosting cardiovascular health (Villareal et al. 2017). In patients with insulin resistance, it was recognized that the combination between anaerobic isometric exercise and regular exercise has better valuable impacts than regular exercise alone to increase insulin sensitivity and glucose tolerance while reducing body fat (Villareal et al. 2017).

In resting conditions, the complex antioxidant ROS protection mechanisms are often not enough to avoid oxidative stress during or after exercise. Anaerobic exercise is sometimes characterized as a short-term, physical activity with high intensity and often as intense exercise. All types of anaerobic activity enhance ROS production and cause oxidative stress. As oxygen usage is increased to a lesser extent during and after anaerobic exercise than in aerobic workouts (Nocella et al. 2019).

Activation of respiration in mitochondria is not the major endogenous cause to produce ROS. Instead, anaerobic exercise-induced increases in ROS are proposed to be derived primarily from the active generation of radicals by XO and NOX as well as from phagocytic respiratory burst and prostanoid metabolism, disruption of iron-containing proteins, and calcium homeostasis loss. For example, XO, a major contributory enzyme to ROS formation during exercise, is produced by ischemia-induced xanthine dehydrogenase proteolysis which takes place during strenuous exercise; its use of molecular oxygen as the electron acceptor results in the production of O₂^•- and H₂O₂ (Veskoukis et al. 2012).

Hormesis is defined by a dose-response connection in which low-dose stimulation results in several positive physiological responses, but high-dose stimulation has harmful consequences. Then, the hormesis concept has been generalized to “adaptive response”, in which living organisms chronically exposed to low-dose hazardous substances become resistant to subsequent high-dose exposure to the same stimulant (Reuter et al. 2010). In other words, repeated low-dose stimuli can cause different hormetic adaptive responses, including antioxidant activation, DNA repair function, and immune function. Also, it was thought that mild or moderate exercise-induced oxidative stress may cause hormetic adaptive reactions. Thus, physiological enhancement (in this case, oxidative stress caused by exercise) is necessary for obtaining health-promoting improvement (e.g., improved antioxidant defense) but levels must never go beyond the oxidative harm upper threshold (Calabrese et al. 2011).

Antioxidant supplementation might be advised before or after the stressful or competitive workout to reduce exercise-induced oxidative damage. Also, the rates of oxidant stress triggered by a high intensity or prolonged exercise may overburden the capacities of antioxidant protection (Koyama 2014). For instance, the practice of an acute exercise enhances the expression of SOD2 in the mitochondria of rat skeletal muscle results in an increase in its activity and inhibiting the accumulation of superoxide after practicing exercise (Steinbacher and Eckl 2015) and this could illustrate the hormesis adaptive principle. Also, a greater frequency of multiple diseases is caused by physical inactivity. Normal exercise, on the other hand, is moderately intense and lasting and has several advantageous effects on the body such as enhancing cardiovascular function, partially due to a nitric oxide-mediated adaptation (Radak et al. 2019).

Antioxidants in high concentrations may have pro-oxidant effects (Yang et al. 2018a) and excessive antioxidants can have dangerous consequences. For example, small but continuous production of ROS expression during physical exercise enhances antioxidant defenses and induces expression of antioxidant enzymes; The supplementation with vitamin C increases stamina in humans and rats (Di Meo et al. 2016) and decreases some of the improved skeletal muscle adaptations after acute exercise (Morrison et al. 2015). Although physiological antioxidant doses may be beneficial, excessive antioxidation may have deleterious implications because the “remodeling” of exercised skeletal muscles depends on reactive oxygen and nitrogen signaling (Merry and Ristow 2016). The duration of antioxidant effects can also be temporary. For instance, in pre-and stage1 hypertensive postmenopausal women, the biomarker of oxidant DNA damage was mitigated by regular consumption of blueberries for four weeks, but these effects were not discovered after 8 weeks (Johnson et al. 2017).

Mindfulness and stress control

Permanent psychological stress (such as work-related stress, marital stress, caring for a sick spouse, or chronic stress associated psychological condition) and negative emotions, independently of other risk factors, have adverse effects on cardiovascular health and increase the risk of arrhythmias (Kivimäki and Steptoe 2018). It was found that these psychosocial factors were the third most important risk factors for MI following smoking and high Apolipoprotein B/ apolipoprotein A- I. A meta-analysis indicates that the risk of low cardiovascular prognosis is almost doubled by depression after MI (Lichtman et al. 2014). The mechanism for this is by affecting the hypothalamic, pituitary-adrenal axis, and autonomous nervous system leading to an elevation in plasma stress hormones (for example, catecholamines and corticosteroid) causing the change in blood pressure and both immune and platelet response and finally stimulate the oxidative stress and inflammation (Carney and Freedland 2017).

In this regard, excessive endogenous production or increased exogenous catecholamine administration has been found to induce cardiotoxicity (Li et al. 2020). In this regard, the pathogenesis of cardiac damage has been reported to link to the accumulation of intracellular Ca²⁺ through induced oxidative mechanisms by catecholamines (Costa et al. 2011). By oxidation of catecholamines, unstable catecholamines-O-quinones are produced that in turn converted into the respective adrenochromes and subsequently oxygen-free radicals such as superoxide radicals are produced. By the action of SOD, the superoxide radicals can be reduced to hydrogen peroxide, which damages the membrane integrity. Superoxide radical was suggested to cause damage in cardiomyopathy caused by catecholamine (Pelliccia et al. 2017). In conjunction with the concomitant production of reactive intermediates and free radicals by enzymatic or metal-catalyzed auto-oxidation of catecholamine, this leads to their toxicities which affect particularly heart tissues (Yang et al. 2018b). Additionally, norepinephrine injection causing the cardiac dysfunction in jeopardized myocardium is due to the elevation of the cardioinhibitory cytokines which may be produced as an adaptive response (Neri et al. 2015).

Concerning the relationship between glucocorticoids and oxidative stress, a meta-analysis shows that, depending on the duration of the therapy, glucocorticoids have been substantially induced oxidative stress. Essentially, the heart was the least tissue vulnerable to glucocorticoids induced oxidative stress while the brain is the most vulnerable to this stress. However, in studies involving both genders, the impact size was greater (1) relative only to males, (2) when corticosterone was used instead of dexamethasone, and (3) in juveniles rather than adults (Costantini et al. 2011).

High cortisol levels have been associated with increased levels of oxidative damage (Joergensen et al. 2011). During mood episodes, this allostatic load causes damage which is hypothesized to make an individual more vulnerable to develop the following episode and somatic disease at higher risk (Grande et al. 2012). Besides, increased cortisol secretion with chronic inflammation of low-grade decreases eNOS expression and NO formation (Bernatova 2014). Depression increased the concentration of inflammatory markers and endothelial dysfunction (Huffman et al. 2013). Experimentally, persistent stress has been found to cause dramatic changes in heart function such as fibrous tissue accumulation in the left ventricular myocardium, left ventricular diastolic damage, and maladaptive cardiac hypertrophy. Also, there was elevated plaque formation in the coronary arteries in response to atherosclerosis, alteration in the heart electrical conduction system (including reduced myocardial refractoriness and diminished conduction), and raised cardiac arrhythmias risk (Crestani 2016).

Conclusion

Conclusively, throughout this review, we have presented evidence in the literature indicating that cardiovascular diseases as one of the leading reasons for global death and many research studies to discover the symptoms, risk factors, effective tools in diagnosis, cellular and molecular mechanisms as well as laboratory biomarkers and finally targeting cardiovascular disease with the effective therapy focusing on oxidative stress and inflammation (as described in Fig. 10). Also, this review covers the area of using miRNA and omics technologies in understanding the cellular and molecular mechanisms underlying several cardiovascular diseases with detecting and hope to overcome their challenges. Dyslipidemia, smoking, hypertension, diabetes mellitus, and chronic kidney disease are well-documented as risk factors for cardiovascular diseases which ultimately lead to oxidative stress and stimulate inflammation. Therefore, natural or synthetic antioxidants and anti-inflammatory agents are recommended to improve cardiovascular health but sometimes the antioxidants targeting the mitochondria are significant to mitigate cardiovascular disease. Besides, a healthy lifestyle includes ideal calorie intake and healthy food as well as good psychological status, with no smoking, is of significant positive impact to prevent or treat cardiovascular dysfunction. There is a need to study both molecular and cellular mechanisms of different compounds that showed therapeutic or preventive effects against CVD. Also, more research is needed to manage different risk factors during the treatment of CVD by the discovery of new diagnostic or prognostic makers using several clinical trials.

Fig. 10

The overall diagram includes the symptoms, risk factors, diagnosis, cellular and molecular mechanisms as well as laboratory biomarkers and finally targeting cardiovascular disease with the effective therapy focusing on oxidative stress and inflammation