A Review on the Potential Use of Medicinal Plants From Asteraceae and Lamiaceae Plant Family in Cardiovascular Diseases

Cardiovascular diseases are one of the most prevalent diseases worldwide, and its rate of mortality is rising annually. In accordance with the current condition, studies on medicinal plants upon their activity on cardiovascular diseases are often being encouraged to be used in cardiovascular disease management, due to the availability of medicinal values in certain dedicated plants. This review was conducted based on two plant families, which are Asteraceae and Lamiaceae, to study on their action in cardiovascular disease relieving activities, to review the relationship between the phytochemistry of Asteraceae and Lamiaceae families and their effect on cardiovascular diseases, and to study their toxicology. The medicinal plants from these plant family groups are collected based on their effects on the mechanisms that affect the cardiovascular-related disease which are an antioxidant activity, anti-hyperlipidemic or hypocholesterolemia, vasorelaxant effect, antithrombotic action, and diuresis effect. In reference to various studies, the journals that conducted in vivo or in vitro experiments, which were used to prove the specific mechanisms, are included in this review. This is to ensure that the scientific value and the phytochemicals of the involved plants can be seen based on their activity. As a result, various plant species from both Asteraceae and Lamiaceae plant family have been identified and collected based on their study that has proven their effectiveness and uses in cardiovascular diseases. Most of the plants have an antioxidant effect, followed by anti-hyperlipidemia, vasorelaxant, antithrombotic, and diuretic effect from the most available to least available studies, respectively. These are the mechanisms that contribute to various cardiovascular diseases, such as heart attack, stroke, coronary heart disease, and hypertension. Further studies can be conducted on these plant species by identifying their ability and capability to be developed into a new drug or to be used as a medicinal plant in treating various cardiovascular diseases.


INTRODUCTION
Cardiovascular diseases (CVD) are known as the most frequent and common cause of death worldwide. World Health Organization (WHO) reported that the total number of people who died from CVDs in 2012 was estimated to be around 17.5 million people representing 31% worldwide population. Disorders of heart and blood vessels, including coronary heart disease (CHD), cerebrovascular disease (stroke), increase in blood pressure (hypertension) and myocardial infarction are the precursor that causes CVD (Rastogi et al., 2016). CVD diseases involve the cardiovascular system that comprises of heart and veins. They are the main source of death universally, and its incidence is rising rapidly globally (Gaziano et al., 2010).
CVD diseases that often being suffered by people are heart failure, coronary heart disease (CHD), stroke, myocardial infarction, and hypertension. CHD and stroke, which responsible for 80% of CVD patients' death, are caused by the lack of oxygen to the brain and heart. The accumulation of fatty deposits within the blood vessel causes the blocking of cerebral and coronary arteries hence narrows their pathway size (Roth et al., 2017). CHD contributes to almost 75% of worldwide death, which occurs both in low-and middle-income countries, due to few factors such as their socio-economy variations and risk factors, due to lifestyle modification (Gaziano et al., 2010).
Heart failure is caused by any functional or structural damage to ventricular filling or in the blood ejection (Klein et al., 2003). It is known as a leading cause of mortality in the western globe and tends to develop when cardiac injury or cardiac insult impairs the heart's ability to maintain and pump tissue perfusion (Lymperopoulos et al., 2013). Hypertension, which is also known as a common CVD, is a crucial concern in health in diverse parts of the world. When the arterial pressure rises above 140/90 mm Hg., it is known as arterial hypertension (Malik et al., 2018).
Stroke is a heterogeneous disease, which includes the hemorrhage of cerebral and the pathogenic subtypes of ischemic stroke (Sacco et al., 2013). In the contribution of the major cause of death, stroke is one of the lead diseases. Among the stroke cases, 85% of them are ischemic stroke, and the other 15% is the hemorrhage stroke, which is also known as an intracerebral stroke (Woodruff et al., 2011). A clinical study shows that warfarin is being effective in preventing ischemic stroke in patients that are suffering from atrial fibrillation, which has reduced the risk of intracranial hemorrhage (Go et al., 2003). Hemorrhage is the rupture of the blood vessel that causes the blood to escape from its blood vessel. One of the main causes of stroke is due to blood coagulation. When the clotting blood accumulates in the blood vessel, the blood refuses to flow to the brain, and the brain tends to be lack of oxygen that leads to ischemic stroke. In this condition, an anticoagulant will avoid the blood from clotting and allow the ease of blood flow throughout the body and brain from the heart. Based on these regards, plants with anticoagulant activity will help treat cardiovascular diseases of these mechanisms.
Throughout human history, medicinal plants have always been used as medicine to treat various diseases. Almost 80% who live in developed countries are said to be depended on the practice of traditional medicine (Abdala et al., 2012). A report from the World Health Organization (WHO) comes out with a percentage of 80% of the global population tend to rely on traditional medicines. Most of the therapies use extracts and active compounds of the medicinal plant (Craig, 1999). Currently, there is a rise in medicinal plant consumption in the world, due to the proven effectiveness of medicinal plants, in curing certain diseases and claims that shows it is safe to be used (Perez Gutierrez and Baez, 2009). Medicinal plants play a major role in medication since the beginning of human civilization and also contribute to the manufacturing of drugs these days (Rastogi et al., 2016).
Asteraceae plant family is also used to be known as the Compositae plant family, is known as one of the largest plant families with thousands of plant species. Its large production as angiosperm phylogeny is in Asterideae. The Asteraceae plant family consists of 24,000 accepted species. It also has about 1,600 to 1,700 of its genera is distributed around the world, excluding Antarctica. This family is also known as a cosmopolitan family, as it has a great concentration of species in different areas such as temperate, cold-temperate, and subtropical. Asteraceae consists of three subfamilies; Asteroideae, Barnadesioideae, and Cichorioideae (Medeiros-Neves et al., 2018). The Lamiaceae plant family is also called a Labiatae family, which is often uttered as the mint family, and the plant family of flowering plants. They consist of shrubs or herbs which produce and release the aromatic smell, which consists of more than 3,000 species in the Lamiaceae plant family. The largest genera of Lamiaceae plant family are Salvia, Scutellaria, and Stachys (Cantino et al., 1992).
Plant species in Asteraceae and Lamiaceae family are being used to cured various diseases. Satureja species exhibits analgesic, antimicrobial, antiviral, antioxidant, antiproliferative, antiinflammatory, and vasodilatory activities (Momtaz and Abdollahi, 2008). Meanwhile, Crassocephalum crepidioides (Benth.) S. Moore were used to cure epilepsy, indigestion, hepatotoxicity, swollen lips, tumor, and sleeping sickness (Bahar et al., 2016). Despite their variation in botanical features and traditional values, both Asteraceae and Lamiaceae plant family species exhibits mechanisms of improving cardiovascular disease. The seeds of Gundelia tournefortti L. (Asteraceae) are often used as pickles, and it is an effective diuretic (Çoruh et al., 2007). Achillea millefolium L., which is a plant species from the Asteraceae plant family, also exhibited diuretics effect in a hypertension group (De Souza et al., 2013). It is often found in Brazil and used as the Brazilian folk medicine, usually for kidney and heart diseases. Emilia praetermissa Milne-Redh. reduced hyperlipidemic conditions as an anticoagulant agent through a clinical study (Memariani et al., 2018). Salvia miltiorrhiza Bunge exerts the potential vasodilator effect on the cardiovascular system (Li et al., 1990). S. miltiorrhiza lowered whole blood viscosity, improved the peripheral circulation, and fastened erythropoiesis of erythrocytes (Lei and Chiou, 1986).
Medicinal plants are currently being used in developing a new hypertension drug, and one of them is Marrubium vulgare L.
from Lamiaceae plant family. The crude oil of the plant was examined its hypotensive effect, and due to the presence of diterpenoids in the plant, it has potential cardiovascular activity, which was caused due to relaxation of vessels and reduces systolic blood pressure which are the mechanisms involved in hypertension (Bardai et al., 2001). The second example is Cynara cardunculus L. (syn. Cynara scolymus L.) from the Asteraceae plant family, which is also known as an artichoke. It is one of the oldest medicinal drugs for its cardiovascular effects. It exhibits a lipid-lowering effect and inhibits the biosynthesis of cholesterol (Fintelmaan, 1996). These drugs prove that medicinal plants can be developed into drugs or for as a treatment for therapeutic purposes. New drugs from the available medicinal plant can treat the disease more efficiently, as a safer and more efficient drug can be discovered in the future, which may benefit the patient (Bardai et al., 2001). Based on the traditional uses and the developed drug, it showed that the plant families have a high potential in alleviating cardiovascular diseases. Thus, an in-depth compilation of the activity and mechanism of the plant family on cardiovascular diseases needs to be examined.
A review on phytochemistry and pharmacological of medicinal plants related to cardiovascular diseases specifically on Asteraceae and Lamiaceae family were conducted by using searching engines such as Google Scholar, Scopus, ScienceDirect, ProQuest, Karger, and Molecule. The literature taken range from the year 1979 to 2018 and was evaluated and tabulated in this review. The keywords used during searching includes "cardiovascular diseases," "coronary heart disease," "stroke," "myocardial infarction," "hypertension," "heart failure," "antioxidant," "anti-hyperlipidemia," "antithrombotic," "medicinal plants," "plants," "herbs," "in vivo," "in vitro" alone and in different combinations. This review specifically focuses on the identification and collection of the information on medicinal plants from the Asteraceae and Lamiaceae family, with proven in vivo or in vitro studies upon cardiovascular diseases. Tables 1 and 2 show the plant species from Asteraceae and Lamiaceae family with their medicinal uses. Tables 3 and 4 are on the mechanisms of the Asteraceae and Lamiaceae family plant species that are involved in cardiovascular diseases. Meanwhile, Figure 1 is composed of chemical compounds derived from the two species that have potential as the lead drug in cardiovascular diseases.

Antioxidant Activity
The chemical substances that reduce or prevent oxidation are known as antioxidants. Antioxidants can resist the free radicals from causing damaging effects in tissues. They are often used to safeguard cerebrovascular diseases (Bandyopadhyay et al., 2007). The oxidative stress that occurs at the cellular level acts as the prime pathogenic factor for cardiovascular diseases. It occurs due to the free radical's toxic being released by the vascular smooth muscle cells and endothelial cells (Fearon and Faux, 2009). Apart from that, cardiovascular diseases are caused by oxidative stress by reactive oxygen species (ROS) such as uncoupled nitric oxide synthases, xanthine oxidase, and NADPH oxidases (Taleb et al., 2018). ROS voluntarily attack and cause oxidative damage to various biomolecules such as lipoproteins, lipids, protein, and DNA.
This oxidative harm is an essential etiological figure that ensnared a few endless human sicknesses. Examples are cardiovascular illnesses, rheumatism, diabetes mellitus, cerebrovascular infections, and malignant growth. The damage of DNA and oxidative stress may be caused by oxidized lowdensity lipoproteins (oxLDL) or by hypercholesterolemia due to individual diet lifestyle (Ceaser et al., 2003). One of the lead causes of atherosclerosis is oxygen-free radicals that reduce the cells' capacity to inhibit the oxidation. This can leads to fatal inflammation disorder.
Achillea tenuifolia Lam. is known for its free radical scavenging activity. The ferric thiocyanate test was conducted to determine the antioxidant activity of A. tenuifolia extract (ATE) by measuring peroxide concentration during the early stage of lipid peroxidation (Ardestani and Yazdanparast, 2007). ATE concentration of 200 and 400 µg/mL suppress the lipid peroxidation by the extension on the lag phase and the reduction of the propagation rate, which reflects the typical chain-breaking antioxidant characteristics. The activity was determined using a linoleic acid system. The peroxidation activity was measured using the thiocyanate method by using the absorbance at 500 nm to determine the peroxide values. The study showed that the ATE contained 55 mg ascorbic acid equivalents per gram of extract with the EC 50 value of 55 µg/mL (Ardestani and Yazdanparast, 2007). Besides consists of gallic acid (1) and catechin (2), this plant also contains phenols and flavonoid, which induce the antioxidant activity in nature (Khafagy et al., 1976). The methanolic extract of A. melampodina subsp. deserti (Boiss.) Eig in the concentration of 25, 50, and 100 µg/mL showed more significant DPPH radical scavenging activity, compared to the positive controls, L-ascorbic acid, and butylated hydroxytoluene, BHT (Shahat et al., 2014). The DPPH radical scavenging activity and chelating effect of the plant were concentration-dependent. The plant extract at the concentration of 400 µg/mL showed a 100% chelating effect. The ferrous ion chelating effect of the extract was measured to determine the capacity of the extract to bind to the ferrous ion to catalyze oxidation in lipid peroxidation. The extract also possessed superoxide anion radicals scavenging capacity. It has a potent anion scavenging power at each concentration tested with a range from 25 µg/mL to 400 µg/mL (Shahat et al., 2014).
Artemisia absinthium L. methanolic (MAB) extract at the concentration from 25 to 100 µg/mL showed scavenging activity on superoxide anion radicals produced from the PMS-NADH system (Bora and Sharma, 2011). When the MAB was administered orally at doses of 100 or 200 mg/kg, it restored superoxide dismutase (SOD) and glutathione (GSH) levels and decreased the thiobarbituric acid reactive substances (TBARS) level. As a whole, it causes inhibitory activity on oxidative stress induced by cerebral ischemia and reperfusion. GSH is known as a central component in the antioxidant and known as the defense cells. It acts by detoxifying ROS directly and as a substrate for various peroxides (Bora and Sharma, 2011). The plant extract consists of quercetin (3), rutin, and vanillic acids (4). It was reported that the plant manages to alleviate stroke disease by reducing SOD activity in the serum (Spranger et al., 1997). Its antioxidant activity has potential in the acute treatment of cerebral ischemia.
Ballota glandulosissima Hub. -Mor. and Patzak is a Turkish Ballota species, collected from Kumluca. The aerial parts of B. glandulosissima were extracted using ethanolic extract and were determined its antioxidant activity via in vitro (Citoglu et al., 2004). The extract showed remarkable anti-superoxide anion formation by inhibiting the activity with an IC 50 value of 0.51 mg/mL. In inhibiting lipid peroxidation, the extract exhibited a  strong inhibitory capacity and potent scavenging property (IC 50 , 15 mg/mL) compared to a-tocopherol (IC 50 , 3 mg/mL) (Citoglu et al., 2004). The antioxidant activity of methanolic extract of aerial part of C. crepidioides (Benth.) S. Moore was determined by measuring its total phenol and flavonoid content, reducing capacity and radical scavenging activity on DPPH assay (Bahar et al., 2016). The plant consisted of various phytochemicals such as flavonoids, alkaloids, tannins, saponins, glycosides, and reducing sugar which, contributed to the extract's antioxidant activity. The activity reported was lower (IC 50 : 130.32 µg/mL) compared to ascorbic acid (IC 50 : 11.24 µg/mL). The aerial part extract of the plant consists of gallic acid (1) and quercetin (3), which tends to cause the antioxidant effect (Bahar et al., 2016).
Dracocephalum moldavica L. contains antioxidant compounds with cardioprotective effects (Jiang et al., 2014). The total flavonoid extract (5 µg/mL) from D. moldavica pretreatment had caused improvement in the heart rate and coronary flow by decreasing lactate dehydrogenase levels, creatinine kinase levels, and caused a rise on left ventricular developed pressure. In the concentration of higher than 70 mg/L, the total flavonoid extract exhibited a higher DPPH radical scavenging activity than vitamin E. The study showed that D. moldavica exhibited protection against myocardial ischemia/ reperfusion(I/R)-induced injury by enhancing GSH/GSSG ratio and SOD activity and attenuating malondialdehyde (MDA) production (Jiang et al., 2014). The ethanolic extract of H. leucocephalum Ausfeld aerial parts showed an antioxidant effect via in vitro assay. The extract exhibited antioxidant activity with an IC 50 value of 69.94 ± 0.17 mg/mL. The high amount of phenolic compounds from this plant showed a sufficient antioxidant activity in the DPPH assay (Goldansaz et al., 2018).
Lavandula angustifolia Mill. from the Lamiaceae family consists of essential oil that can inhibit isoproterenol-induced myocardial infarction in rats (Ezzoubi et al., 2014). It protected the myocardium against isoproterenol-induced myocardial infarction at the concentration of 20 mg/kg of the essential oil. This amount of oil had caused the reduction in the ST-elevation  Aerial parts Ethanolic extract Sesquiterpene lactones, polyphenols, and flavonoids.

In vivo
The extract at a dose of 400 mg/kg showed a significant decrease in the levels of serum cholesterol, triglycerides, and LDL. It also significantly decreased hepatic total cholesterol and triglycerides. (Mais et al., 2016) A. millefolium L. Aerial parts (leaves, stalks, and stems) Hydroethanolic extract (HEAM), Dichloromethane (DCM), and armetin Flavonoid

In vivo
With the dose of 300 mg/kg of HEAM, it increased the diuresis around 30-60% between 4 and 8 h after administration. The diuresis effect decreased systemic vascular resistance. The extract also reduced blood volume and cardiac output. A single dose of HEAM (100 mg/kg), which was administered to the rats 3 h before measurement, showed a lower MAP reading by 13 ± 1 mm Hg. Increasing the dose to 300 mg/kg, decreased MAP by 14 ± 3 mm Hg.

In vitro
At high concentrations (200 and 400 kg/mL), ASE suppressed lipid oxidation, by extending the lag phase and reducing the propagation rate. It reflects a typical characteristic of a chainbreaking antioxidant, similar to that of known antioxidants. (Ardestani and Yazdanparast, 2007) Ageratum conyzoides (L.) L.

In vitro
The extract showed a significant (p < 0.05) activity at the dose of 100 mg/mL in the scavenging of superoxide anion radical. Pre-treatment of ischemic brain mouse with the extract significantly (p < 0.05) decreased the elevated TBARS concentration in brain mitochondrial and supernatant fractions as compared to the control group. Reducing power of the extract data suggests that it contributes significantly to the observed antioxidant effect. (Bora and Sharma, 2011) Artemisia campestris L.

In vivo
The extract at the dose of 150 mg/kg/day prevented hypertension on hypertensive rats and reduced SBP from 172 mm Hg to 144 mm Hg. At the dose of 40 mg/kg, the extract reduced SBP, DBP, and MAP, without affecting the heart rate. The extract (10 −2 -2 mg/mL) relaxed the pre-contracted aorta by 95.8 ± 1.3%. (Dib et al., 2017) Baccharis trimera (Less.) DC

In vitro
The aqueous extract showed higher efficiency in eliminating DPPH radical with an IC 50 value of 415 ± 12.1 mg/mL. The extract was capable of reducing deoxyribose damage at all concentrations by its ability to chelate iron by greater than 50% at the extract concentration of 100 mg/mL. (Sabir et al., 2017) Bidens pilosa L. Leaf Aqueous and methylene chloride extracts Flavonoids, alkaloids, saponins, phenyl acetylenes, and terpenes

In vivo
Aqueous extract (150 or 350 mg/kg) and methylene chloride extract (150 mg/kg or 300 mg/kg) of B. pilosa completely blocked the elevation of blood pressure in fructose-treated rats and provoked a decline toward control values. The extracts reversed the increase in SBP. (Dimo et al., 2001) Chamaemelum nobile (L.) All.
Whole plant Aqueous extract -In vitro and Single oral administration of the extract (140 mg/kg) produced a significant reduction in SBP. Daily oral administration of the extract (140 mg/kg) during three weeks, produced a significant reduction in SBP in day eight of treatment. (Zeggwagh et al., 2009)

Mechanism of Action References in vivo
The extract produced a significant increase in urinary output and electrolytes excretion. Chromolaena odorata (L.) R. M. King and H. Rob.

Leaves
Aqueous extract -In vivo 100 mg/kg of aqueous extract reduced triglycerides, LDL, VLDL, non-HDL, and total cholesterol. The HDL-C level of the treated animals was significantly higher. (Ikewuchi and Ikewuchi, 2011) Chrysanthemum x morifolium Ramat. Hemsl.

Polyphenols
In vivo Polyphenol-rich CME alleviated hypertensive cardiac hypertrophy in rats through the reduction of blood pressure. Administration of CME at the dose of 75-150 mg/kg for four weeks lowered the SBP. Increasing concentration of the methanolic extract increased its DPPH radical scavenging activity. The Wistar albino rats were administered with plant extract (150 and 300 mg/kg/day) orally. It significantly reduced the serum total cholesterol, triglycerides, LDL-C, VLDL-C levels, and significantly increased serum HDL-C level compared with a positive control group. The dose of 300 mg/kg showed significant (p < 0.01) antihyperlipidemic activity compared with the positive control group. (Bahar et al., 2016) C. cardunculus L.

Leaf Quercetin (3) Phenols and flavonoids
In vitro and in vivo The extract exhibited a free radical scavenging effect. Hyperlipidemic rat administered with the extract of 150 to 600 mg/kg decreased triglyceride and LDL-C levels. It also reduced HMG-CoA reductase enzyme activity, hence reduced the formation of VLDL from the liver. (Mocelin et al., 2016) Eclipta prostrata (L.) L.

Flavonoids and tannins
In vitro In vivo The extract inhibited thrombin and factor Xa amidolytic activities in the presence of antithrombin. The plant preparation inhibits plasma clot formation in aPTT at the concentration as low as 390 mg/mL of standardized human blood plasma, and in PT test at the concentration of 1.56 mg/mL. The strong anticoagulant effect was observed after 40 min after the administration, with the clotting time almost three times longer than control measurement. (Pawlaczyk et al., 2011) Flaveria bidentis (L.) Kuntze

Flavonoids
In vitro QTS has higher activity than ATS in activating heparin cofactor II (HCII), indicating that these flavonoids act as agonists of this inhibitor. The flavonoids also increased PT with a concentration of 1 mM of QTS (25.2 ± 0.8 s, p < 0.01) and ATS (22.2 ± 0.7 s, p < 0.04). It also prolonged aPTT at the concentration of 112 ± 11 and 53 ± 2, respectively. (Guglielmone et al., 2002) G. tournefortti L.

Seeds Tyramine Saponin and alkaloid
In vivo The oil extract (90 mg/kg) possessed a hypolipidemic effect by reducing plasma total lipid, total cholesterol, VLDL-cholesterol, LDL-cholesterol, and atherogenic indices. It also increased the HDL value and reduced the total cholesterol level in the liver.  The extracts exhibited scavenging activity towards DPPH radicals. (Goldansaz et al., 2018) Inula racemosa Hook F.

Roots
Alcohol extract (essential oil of the roots), phenyl acetonitrile and phenyl ethanol Sesquiterpenes and phenolics

In vivo
IrA decreased total cholesterol, triglycerides, LDL-C, and the atherogenic index, and increased HDL-C compared with the positive control. It also reduced GSH in both the tested tissues, levels of endogenous antioxidants SOD and GPX in the heart. It inhibited lipid peroxidation, and reduced lipid uptake, resulting in a reduction of fatty streak formation, via decreased foam cell formation. (Mangathayaru et al., 2009) L. decurrens (Vahl) Hepper and J. R. I.Wood.

In vitro
The extract exhibited antioxidant properties with an IC 50 value of 59.12 ± 3.14 µg/mL. (Schneider et al., 2015) (Continued) of the myocardial infarction situation, resembled its effectiveness in cardiovascular disease, and indicated its protective effects on cell membrane functions (Ezzoubi et al., 2014). The essential oils and subfractions of M. macrosiphon Coss. methanolic extract were examined their antioxidative properties via in vitro study (Amiri, 2011). In examining the effect of M. macrosiphon on DPPH assay, the polar subfraction of the flowering stage was more potent with an EC 50 value of 57.0 ± 0.6 mg/mL. In contrast, the essential oil of the flowering stage was more potent (EC 50 : 91.7 ± 1.2 mg/mL) in inhibiting a-carotene oxidation with almost similar inhibitory activity compared to the positive control, BHT. The oxidation of a-carotene was determined by observing its discoloration caused by coupled oxidation of linoleic acid and acarotene that generates free radicals.
The phenolic compounds isolated from the ethanolic extract of the whole plant of O. vulgare L. were determined their antioxidant activity. From the study, O. vulgare consists of phenol compounds such as 2,5-dihydroxybenzoic acid, 3,4dihydrobenzoic acid, rosmarinic acid (5), origanoside, maltol, E-caffeic acid (6), apigenin (7), luteolin (8), and didymin (Zhang et al., 2014). Based on the in vitro test, the phenolic compounds of O. vulgare showed potent antioxidant activity. The SC 50 values of the compounds ranged from 16.7 ± 1.1 to 221.8 ± 49.0 µM. The scavenging activity of the compound that consists of 3,4dihydroxyphenyl and gastrodin moiety was higher than its positive control, the ascorbic acid. The highest radical scavenging activities were exhibited by compounds with danshensu moieties with SC 50 values 17.5 ± 1.1 µM and 16.7 ± 1.1 µM. The phenolic structure is responsible for the scavenging activity by donating the hydroxyl group to the free radicals (Graf, 1992). The ferric reduced antioxidant power (FRAP) assay also showed similar antioxidant activity of the phenolic compounds.

In vivo
The extract at the dose of 125, 250, or 500 mg/kg decreased the total cholesterol of rats. Sphaeranthus indicus L.

Flower
Ethanolic extract Tannin In vivo The extract of dose 500 mg/kg/day given in rat orally for eight days caused a decrease in body weight, total cholesterol, triglycerides, LDL, and VLDL. It showed a rise in HDL level resembling its use in atherosclerosis conditions. (Pande and Dubey, 2009) Tagetes erecta L.

In vivo
The citric acid (24) reduced the blood pressure of normotensive rats in a dose-dependent manner. It caused 17-21% and 32-35% fall in MABP at the corresponding doses of 3 and 30 mg/kg, respectively. (Saleem et al., 2004) T. vulgare L. Leaves Plant extract -In vivo Administration of 10 mg/kg of the leaf extract caused an increase in urine output. The levels of Na + and K + in the urine increased, but the plasma Na + and K + were not affected in this activity. (Lahlou et al., 2007) Tridax procumbens (L.) L.

In vitro
The sulfated polysaccharides prolonged aPTT (113 s) at a dose of 100 mg/mL, which was approximately 4.0-fold compared with the saline group. (Naqash and Nazeer, 2011) Vernonia elaeagnifolia DC.

In vivo
The extract restored the levels of LDL and HDL cholesterol of albino rabbits. (Sultana et al., 2017)  In vivo The extract inhibited lipid peroxidation with an IC 50 value of 12 to 20 mg/mL. (Sever, 2000;Citoglu et al., 2004) Clerodendrum volubile P. Beauv

In vivo
The extract (250 and 500 mg/kg) significantly lowered the total cholesterol, LDL, VLDL, and triglycerides, and increased HDL level dose-dependently, in both phyto-preventive and curative animals.

Plant extract Flavonoid
In vitro The flavonoids fraction, at the concentration of more than 70 mg/L, exhibited a higher DPPH radical scavenging activity than vitamin E. The flavonoids fraction also possessed scavenging activity on DPPH, hydroxyl radicals, and superoxide anion radicals. (Jiang et al., 2014) Isodon rugosus (Wall. ex Benth) Codd

Aerial parts
Crude extract -In vivo and in vitro The crude extract (0.01-0.3 mg/mL) possessed a relaxant effect on isolated rabbit jejunum, trachea, and aorta preparations. The mechanism of action was assumed to be by the Ca 2+ channel blockade. (Janbaz et al., 2014) Lagenaria siceraria (Mol.) Standl

Fruit C-glycosides Flavone
In vivo L-NAME was used to induce hypertension in rats. Concomitant treatment of L. siceraria fruit powder (LS) and L-NAME for 28 days reduced cholesterol level but did not reduce triglycerides levels. It also reduced SBP, DBP, and MABP significantly. LS, as well as L-arginine treatment, produced significant (p <0.001) attenuation of the hypertensive effect of L-NAME. (Mali et al., 2012) Lallemantia royleana Benth. in Wall.

In vivo
Administration of the seeds for 12 weeks decreased (p < 0.05) the rabbit's total serum cholesterol and triglycerides. It also significantly decreased LDL-C and HDL-C of the hypercholesterolemic group (p < 0.05). (Ghannadi et al., 2015) Lavandula angustifolia Mill.

In vivo
The essential oil (10 mg/kg) significantly decreased heart to body weight ratio (p < 0.001). Treatment with 10 and 20 mg/ kg of essential oil demonstrated a profound reduction (p < 0.001) in the ST-segment elevation. (Ziaee et al., 2015) Lavandula stoechas L.

Aerial parts
Ethanolic extract -

In vitro
The extract exhibited antioxidant activity by scavenging DPPH with an IC 50 value of 1.2 mg/mL while the IC 50 value of the reference standard, BHT was 0.2 mg/mL.  LCRE at the dose of 1.0 to 2.0 mg/mL was infused intracoronary for 10 min before mapping its epicardial potential. It reduced the left ventricular pressure in a dosedependent manner and elevated the relative coronary flow.

In vivo
The ethanolic extract of leaves (200 and 400 mg/kg) showed significant inhibition against dexamethasone-induced hyperlipidemia in rats by maintaining the serum levels of cholesterol and triglycerides near to normal levels. (Kumar, 2016) M. officinalis L. Leaves Hydroxycinnamic acid derivatives (rosmarinic acid (5) and caffeic acids (6))

In vitro
The methanolic extract of its flowering stage possessed higher activity in inhibiting a-carotene oxidation with an EC 50 value of 57.0 ± 0.6 mg/mL. (Amiri, 2011) O. vulgare L.

In vivo
MRC (50 and 100 mg/kg) reduced SBP and heart rate of the mice via the subcutaneous route. The MRC reduced BP due to the dilation of the blood vessel decreased in cardiac output. It also has suppressive actions to contractions. (Matsubara et al., 1999) Whole plant Sinensetin (17), eupatorin (26), flavonoid -

In vitro
Sinensetin (17) (0.03-2.11 µM) caused concentrationdependent vasorelaxation of phenylephrine-contracted endothelium-intact aortic rings. O. aristatus caused aortic ring that was pre-contracted with phenylephrine in the presence and absence of endothelium to be relaxed. It also caused relaxation to the aortic ring that was pre-contracted with potassium chloride in the endothelium-intact aortic ring.  (10 −2 -1 mg/mL) inhibited aorta smooth muscle contraction suggesting calcium channel blocking action with a major inhibitory effect on L-type voltage-operated Ca 2+ channels. Pogostemon elsholtzioides Benth.

In vitro
The essential oil of P. elsholtzioides induced dose-dependent vasodilation in pre-contracted aortic rings against contraction evoked by Phe (10 −3 M). Injection of the essential oil at the dose level 20 mg/kg induced a significant decrease in MAP and heart rate. The aqueous extract showed a substantial increase in the HDL level. The extract exhibited radical scavenging activity towards superoxide, hydroxyl, and hydrogen peroxide. (Zargar et al., 2017) R. officinalis L.
Leaves n-butanol extract Flavonoids and phenolic

Leaves and stem
Aqueous plant extract -

In vivo
Intravenous consumption of 1 and 2 g/kg of the extract produced a significant increase in diuresis. It increased the urinary excretion of potassium and chloride. High tubular concentrations of potassium stimulated the activity of the Na + / K + ATPase pump in the basolateral membrane of the tubular epithelial cells, decreasing the sodium concentration in the urine. (Ramirez et al., 2006) Satureja cuneifolia Ten. (syn. Satureja obovata Lag.)

In vivo
Administration of 50 to 150 mg/kg of the extract for ten days significantly reduced the serum levels of cholesterol and triglycerides in hyperlipidemic rats dose-dependently. (Rasekh et al., 2001) Thymus saturejoides Coss.

Polyphenolic compound
In vivo and in vitro The extract exhibited a hypolipidemic effect. Injection of 0.2 g/ 100 g of the extract significantly lowered both plasma triglycerides and cholesterol levels after 24 h of treatment. The reduction of plasma total cholesterol was associated with a decrease in the LDL fraction. It suppressed the elevated blood concentrations of triglycerides. (Ramchoun et al., 2012;Khouya et al., 2015) Thymus serpyllum L.

In vivo
The injection via bolus of 100 mg/kg body weight produced a significant decrease in SBP, DBP, and total peripheral (Katalinic et al., 2006;(Continued) ethyl acetate extract of the plant exhibited the strongest activity on ABTS (IC 50 value: 32.7 mg/mL) and DPPH (IC 50 value: 35.5 mg/mL) assay. Based on the Folin-Ciocalteu method, the plant contains total phenol of 76.3 mg chlorogenic acid (11) equivalent per gram of the plant. Whereas, based on the formation of the flavonoid-aluminum complex method, the plant contains a total flavonoid of 11.8 mg quercetin (3) equivalent per gram of the plant. Thus, it was assumed that the antioxidant activity of the plant due to its flavonoids content (Tundis et al., 2012). Silybum marianum (L.) Gaertn. contains silymarin (12), which is one of the polyphenolic antioxidants. Administration of 200 mg/kg silymarin (12) by intraperitoneal on rats reduced ROS level and protected the rats from supra celiac abdominal aorta ischemia or reperfusion injury. (Kocarslan et al., 2016). Administration of 100 mg/kg silymarin (12) on the rats reduced iron and oxidative stress level of the rats' blood. Besides, the phenolic structure of silymarin (12) caused the compound to has a strong scavenger activity towards hypochlorous acid (HOCI). It inhibited hydroxyl radical formation, which is essential for the inhibition of xanthine oxidase activity (Varga et al., 2006). A low concentration of silymarin (12) caused inhibition of the NF-kB pathway by treating and attenuating the inflammatory reaction that stimulates atherosclerosis.

Antihyperlipidemia, Hypolipidemia, and Hypocholesterolemia Activity
The rise in both blood cholesterol and triglyceride that may be due to hereditary factors is known as hyperlipidemia. One of the CVD that is caused by hyperlipidemia is atherosclerosis. It is the condition where the lipids or fat substances which are denoted as plagues hardened the arteries. These plagues will be built up in the walls of arteries and lead to the narrowing of the arteries. It will diminish the ability of blood flow in the artery that usually associated with vascular diseases, heart disease, and stroke (Akinpelu et al., 2016). The role of substance that possesses the antihyperlipidemic effect is to reduce the total cholesterol level in the body by reducing triglycerides, very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). The antihyperlipidemic possessing substance also has a role in increasing the high-density lipoprotein (HDL) level in the body, which is known as the good cholesterol in the body that alleviates the risk of CVD. Achillea arabica Kotschy ethanolic extract was used to test its hypolipidemic effect in animals (Mais et al., 2016). The extract was from the aerial parts of the plant taken during its flowering Thymus zygis L.

In vivo
In the aPTT test, it completely inhibited the plasma clot formation in the concentration of 5.72 mg/mL in the clotting mixtures and prolongs the clotting time at the concentration of 0.18 mg/mL In the PT test, it completely inhibited the clotting process at a concentration of 11.43 mg/mL. (Khouya et al., 2015) Vitex megapotamica (Spreng.) Moldenke

Leaves Crude extract Flavonoid
In vivo The hydroethanolic extract (500 or 1,000 mg/kg/day) significantly reduced the levels of total cholesterol, triglycerides, LDL-C, and the atherogenic index. The atherosclerotic plaque formation was impaired only by the lower dose of the hydroethanolic extract. (Pires et al., 2018) Ziziphora clinopodioides Lam.

In vitro
The extract exhibited relaxation on the vascular smooth muscle cells through intracellular and extracellular Ca 2+ mobilization. It acts on voltage-dependent K + channels. (Senejoux et al., 2010) phase. The high-fat diet was fed to adult male Golden-Syrian hamsters for ten days to cause hyperlipidemia. The dose of 400 mg/kg of the A. arabica ethanolic extract had reduced VLDL, cholesterol, LDL, and triglycerides level in the hamsters' serum. It had no significant effect on HDL. Total cholesterol and triglycerides in the hepatic were also reduced. The plant extract contains flavonoids, sesquiterpene lactones, and polyphenols. Whereas, its essential oil contains a high amount of eucalyptol (13) (10.98%), camphor (14) (12.46%) and piperitone (15) (31.06%). These may act as an inducer for the hypolipidemic effect of A. arabica upon the experimental hyperlipidemic hamster (Mais et al., 2016). Few reports had documented that flavonoids and phenolic compounds have antioxidant, antihyperlipidemic, and antihypertensive activity as their pharmacological effect (Rouhi-Boroujeni et al., 2015).
In vivo study of methanolic extracts of Ageratum conyzoide L. root, leaf, and stem were carried out on rats to examine its hypolipidemic activity (Atawodi et al., 2017). The extracts contain flavonoids, alkaloids, cardiac glycosides, triterpenes, saponins, carbohydrates, and tannins. Meanwhile, the leaf also consists of steroids. Fiber, saponins, and flavonoids have an underlying antihyperlipidemic effect. The methanolic extract in a concentration of 100 mg/kg was treated on rats. The extract reduced serum lipids, which is one of the insulin-releasing factors. Insulin inhibits lipolysis, thus causing a rise in uptake of fatty acids into adipose tissue and triglyceride synthesis. The diabetic rat had shown a significant reduction in total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) levels, and increased high-density lipoprotein cholesterol (HDL-C) (cardioprotective lipid) levels (Atawodi et al., 2017).

FIGURE 1 | Continued
Chromolaena odorata (L.) R. M. King and H.Rob. leaves aqueous extract was examined its atherogenic indices and plasma lipid profiles on rats that have fed loaded with cholesterol (Ikewuchi and Ikewuchi, 2011). The intra-gastric gavages of the plant extract (100 mg/kg body weight) was administered to the rats. As a result, there was a significant reduction in total cholesterol, LDL, non-HDL, VLDL, and plasma's triglyceride levels. The HDL-C level in the plasma was high once being treated with the extract. The extract contains saponin, which was reported to have a hypercholesterolemic activity (Soetan, 2008). The extract significantly reduced (p < 0.05) the atherogenic index of plasma, cardiac risk ration, and atherogenic coefficient compared to the control group. Thus, the study showed that C. odorata could reduce the risk of heart diseases (Ikewuchi and Ikewuchi, 2011).
Ethanolic leaf extract of C. volubile P. Beauv. was evaluated by its anti-hyperlipidemic activity (Akinpelu et al., 2016). Clerodendrum volubile ethanolic leaf extract contains cardiac glycosides, saponins, flavonoids, alkaloids, tannins, and steroids. The extract contains phenolic compounds as the major constituents, followed by flavonoids and alkaloids. The lowest constituent of the extract was tannin, followed by saponin. The extract with a concentration of 250 and 500 mg/kg was administered to the hyperlipidemic animal. The extract significantly reduced the triglycerides, VLDL, total cholesterol, and LDL level in curative and phyto-preventive animals in addition to increased their HDL level (Akinpelu et al., 2016).
The methanolic extract of the aerial parts of C. crepidioides (Benth.) S. Moore had shown an antihyperlipidemic activity (Bahar et al., 2016). The albino rats were induced with a high-fat diet to mimic hyperlipidemia model. The methanolic extract in a concentration of 150 and 300 mg/kg were administered orally to the rats. As a result, the extract increased HDL-C level while reduced VLDL-C, LDL-C, total cholesterol, and triglycerides levels compared to the positive group. The extract in a concentration of 300 mg/kg showed potent antihyperlipidemic activity compared to the positive control group (Bahar et al., 2016).
Cynara cardunculus L. is known for its antiatherogenic and hypolipidemic effects. Hypercholesterolemic rats were fed with C. cardunculus leaves aqueous extract at the amount of 150, 300, and 60 mg/kg (Mocelin et al., 2016). The extracts exhibited DPPH scavenging activity with an IC 50 value of 57.40 ± 2.05 µg/ mL. After four weeks of treatment, the serum lipid profile showed that there was a decrease in total cholesterol and LDL-C levels. The flavonoids and phenols content decreased the activities of acyl-CoA acetyltransferase and HMG-CoA reductase in the hypercholesterolemic rats. It decreased the availability of cholesterol esters to form VLDL, which caused a reduction in the secretion of VLDL from the liver (Mocelin et al., 2016).
Eclipta prostrata (L.) L. leaf extract was measured its hypolipidemic activity (Dhandapani, 2007). The phytochemical screening had shown the presence of saponins, alkaloids, flavonoids, phytosterols, and tannins in the leaf extract. Atherogenic diet caused an increase in total cholesterol and total protein and decreased serum HDL-cholesterol level in rats. Daily administration of the aqueous extract in the dose 100 and 200 mg/kg increased the rats' HDL level and reduced protein level, triglycerides, and total cholesterol significantly. It had also shown an increase in the atherogenic index. The saponins may contribute to the hypolipidemic effect of the plant extract (Dhandapani, 2007).
Emilia praetermissa Mi l ne -R e d h ha d s ho wn it s antihyperlipidemic effect via its aqueous leaf extract. The extract at doses of 100 mg/kg, 200 mg/kg, and 400 mg/kg were fed to male albino rats. As a result, the extract reduced the levels of plasma atherogenic index, total cholesterol, LDL, and triglycerides, and raised the level of HDL significantly when compared with the hyperlipidemic group. The hypolipidemic activity might due to the cholesterol-lowering effect of the extract, which may be portrayed by tannins, terpenoids, and flavonoids content. Terpenoid acts as an intermediate in cholesterol synthesis. It regulates the degradation of HMG-CoA reductase activity, which is the main enzyme in cholesterol synthesis (Ngozi et al., 2013).
Alcohol extract (IrA) and hexane extract (IrH) of Inula racemosa Hook F. roots at the dose of 100 mg/kg was administered to guinea pigs to observe the extracts' hypolipidemic effect (Mangathayaru et al., 2009). IrA showed antihyperlipidemic activity by reducing lipid peroxidation and lipid uptake. It decreased foam cell formation and led to a reduction of fatty streak formation. Meanwhile, IrH exhibited more significant activity in enhancing HDL-C (p < 0.001) than in reducing LDL levels. Based on the effects of the extracts on coronary artery histopathology, IrA and IrH had shown a replacement in a muscular pattern which is the type of primary medial destruction in early atherosclerosis. It also caused the cardiac tissue to be devoid of fatty degeneration. The presence of the phenolic compounds contributes to the inhibition of LDL oxidation and prevent the degradation and uptake of oxidized LDL by macrophages (Mangathayaru et al., 2009).
Launaea intybacea (Jacq.) Beauverd exhibited curative and preventive activity against hyperlipidemia (Devi and Muthu, 2015). Its ethanolic extract of the whole plant reduced cardiac risk ration, plasma lipid, and lipoprotein profile. It increased the HDL level, which responsible for neutralizing atherogenic effects of oxidized LDL, in addition to inhibiting LDL oxidation and reversing cholesterol transport. It also reduced free cholesterol and ester levels. Its lipid-lowering activity was due to its inhibition of hepatic cholesterogenesis or due to its ability to increase fecal sterol excretion (Devi and Muthu, 2015).

Vasorelaxant and Vasodilation Action
Excessive contraction of vessels can cause increases in pressure that may lead to hypertension. Vasorelaxant facilitates the vasodilation of the contracted vessel to ensure the ease of blood flow through the blood vessels. Vascular smooth muscle relaxation is one of the mechanisms for treatment and prevention of hypertension, with most of the treatments were focusing on impeding vascular smooth muscle contraction (Goodman, 1996) Agastache mexicana (Kunth.) Lint. and Epling is a medicinal plant species from the Lamiaceae family that can treat hypertension and anxiety conditions. The antihypertensive activity of the dichloromethane extract of A. mexicana (DEAm) and its isolated compound, ursolic acid were determined in the male rat (Flores-Flores et al., 2016). The extract exhibited relaxant activity on noradrenaline bitartrate 0.1 µM and potassium chloride (KCl) 80 mM pre-contracted aortic rings which suggest that the extract exhibited vasodilation effect through several receptors, such as the augment of free cytosolic Ca 2+ levels. The extract inhibited the vasoconstriction caused by noradrenaline bitartrate and potassium chloride (Hernandez-Abreu et al., 2013). Ursolic acid evoked a significant decrease in systolic blood pressure (SBP) and diastolic blood pressure (DBP) with no change in the hypertensive rat. This action was due to its diuretic effect in relieving the hypertension condition (Somova et al., 2003).
The aqueous extract of Artemisia campestris L. aerial parts (AcAE) has a hypotensive and antihypertensive effect due to its vasodilatory effect (Dib et al., 2017). The extract contains a high amount of polyphenols such as mono-and dicinnamoyl compounds with the highest concentration of 3,5-dicaffeoylquinic (isochlorogenic A) as its constituent. Meanwhile, the major flavonoids in the extract were (5caffeoylquinic) chlorogenic acid (11) and vicenin-2 (apigenin 6,8-di-C-glucoside) (16). Daily administration of 150 mg/kg of AcAE on L-NAME hypertensive rats prevented hypertension by reducing SBP from 170 to 114 mm Hg. The extract at the dose of 40 mg/kg reduced SBP and DBP without affecting heart rate. The extract caused vasorelaxation via inhibition of calcium influx through voltage-operated calcium channels and the calmodulin-NO-sGC-PKG pathway. Besides, the extract also activated intracellular calcium mobilization into the sarcoplasmic reticulum (Dib et al., 2017).
Based on one of the studies on Bidens pilosa L., the plant exhibited a vasorelaxant effect on precontracted rat aorta induced by the KCl (Nguelefack et al., 2005). Besides, it also exhibited vasodilating activity on norepinephrine-induced tonic contraction. The endothelium of the vascular managed to secrete contractile factors and relaxant that caused regulation of vascular tone. The chemical and physical stimulations are responded by the endothelial cells, by producing prostacyclin, nitric oxide, and bradykinin which are the relaxant factors (Corvol et al., 1993;Dimo et al., 2001).
Clinopodium vulgare L. was used in in vivo and in vitro studies to understand its antihypertensive activity (Khan et al., 2018). The administration of C. vulgaris crude extract and fractions on normotensive and high salt-induced hypertensive rats reduced the rats' mean arterial pressure (MAP). It has a distinct effect on hypertensive rats compared to the normotensive rats. At the dose of 1, 3, 10, and 30 mg/kg, the extract had shown an antihypertensive effect in hypertensive rats with the most significant activity exhibited by the extract at the dose of 10 and 30 mg/kg. The vasodilatory effect of the extract (EC 50 :0.27 mg/mL) in the extracted rat aorta was endotheliumdependently. The extracts worked by inhibiting the high K + precontraction and rightward shifted Ca 2+ concentrationresponse curves which have an identical mechanism to verapamil. The antihypertensive effect that was showed by C. vulgaris is due to the vasodilation effect that involves muscarinic receptor-linked NO and activation of tetraethylammonium (TEA)-sensitive K + channels, Ca 2+ antagonism, and prostacyclin. The methanolic extract of the plant consists of quercetin (3) and rutin, which may act as the substance that possesses the vasodilatory effect (Khan et al., 2018).
Flower extract of Chrysanthemum x morifolium Ramat. Hemsl. exhibited a vasodilatory effect by reducing the blood pressure of cardiac hypertrophy rats (Gao et al., 2016). The major phytochemicals in this extract are 4,5-di-caffeoylquinic acid, 3,5dicaffeoylquinic acid, luteolin-7-b-glucoside, 3-chlorogenic acid (11), and apigenin-7-O-glucoside. A range of 75 to 150 mg/kg extract was fed to the rats for four weeks to study the effect of the extract on the rats' SBP. The dose of 150 mg/kg showed a reduction in the SBP, which was about 4% by the second week. One month administration of the extract caused a reduction in the serum-free fatty acid (FFA) by 18.9% to 29.8%, and myocardial FFA level by 5.4% to 16.0%. In addition to the extract activity in inhibiting myocardial hypoxia-inducible factor-1a (HIF-1a) expression, the extract also caused subsequent modulation of some peroxisome proliferatoractivated receptor a (PPARa)-mediated gene expression; a decreased in the glucose transporter-4 (GLUT-4) protein expression and an increased in the pyruvate dehydrogenase kinase-4 (PDK-4) and carnitine palmitoyltransferase-1a (CPT-1a) protein expression. (Gao et al., 2016).
Orthosiphon aristatus (Blume) Miq. contains sinensetin (17), which is essential for vasorelaxation activity (Yam et al., 2016;Yam et al., 2018). The studies measured the vasorelaxant effect of the compound by conducting a pre-contraction aortic ring assay. The presence of antagonists has shown the mechanism of the vasorelaxant effect of sinensetin (17). Sinensetin (17) had exhibited a relaxation effect of potassium chloride-induced endothelium-intact aortic rings and phenylephrine-induced aortic ring with or without the endothelium. The study showed that sinensetin (17) exhibited a vasorelaxant effect via antagonization of aortic ring contraction through direct and indirect vasorelaxation. The pathways that were involved in this vasorelaxant activity were NO/sGC/cGMP pathways. Sinensetin (17) at a dose of 0.262 µg/mL caused the vasodilatory effect (Yam et al., 2016;Yam et al., 2018).
The vasodilatory effect of essential oil of the Pectis brevipedunculata Sch. Bip aerial parts (EOPB) was identified (Pereira et al., 2013). The essential oil is rich with citral content, which consists of neral (18) and geranial (19), followed by limonene and a-pinene. The vasodilator activity of EOPB and citral was measured using aortic rings obtained from Wistar Kyoto (WKY) rats. EOPB and citral exhibited relaxation to the phenylephrine-induced endothelium-intact aortic rings with an IC 50 value of 0.044 ± 0.006% and 0.024 ± 0.004%, respectively. Meanwhile, EOPH and citral exhibited relaxation to the phenylephrine-induced denuded aortic rings with an IC 50 value of 0.093 ± 0.015% and 0.021 ± 0.004%, respectively. The extract mechanism of activity was through the NO/cyclic GMP pathway. Meanwhile, the citral mechanism of activity was by blocking voltage-dependent L-type Ca 2+ channels that reduced calcium influx. The high concentrations of EOPB caused vasorelaxation of endothelium-independent which predominated the endothelium-dependent pathway (Pereira et al., 2013).
Phlomoides bracteosa (Royle ex Benth) Kamelin and Makhm. has few phytochemicals which had the vasorelaxant effects, which are marrubiin (20), phlomeoic acid, and new components (RA and RB) (Khan et al., 2012). The whole plant was powdered and extracted using methanol to produce its extract and examined its activity using rat thoracic aorta. The EC 50 values of 23.4 and 36.7 mg/mL of marrubiin (20) had shown a relaxant effect upon the phenylephrine-induced contraction and inhibited the K + . Marrubiin (20) in the concentration of 3.0 to 10 mg/mL induced rightward shift of the Ca 2+ channels. Marrubiin (20), phlomeoic acid, and RA exhibited a more potent effect against K + -induced contractions, compared with phenylephrine, which indicated that it had a greater efficacy in blocking the voltage-sensitive Ca 2+ channels. Among all four phytochemicals studied, the marrubiin (20) was most potent for its vasodilator activity. It can be used in further studies to test its extent of vasodilation activity in the future (Khan et al., 2012).
Satureja cuneifolia Ten. is a plant species from the Satureja genus. Its constituent, eriodictyol (21), possessed a vasodilatory effect in the rat aorta (De Rojas et al., 1999). The concentration of eriodictyol (21) 10 5 M and 5 × 10 5 M showed the inhibitory effect of calcium chloride, CaCl 2 in the concentration-response curve. It possessed a weak inhibition in the calcium from the sarcoplasmic reticulum whereby showing off a light relaxant effect. The final results of the study indicated that the partial mechanism of the vasodilatory effect was due to its inhibition of enzyme protein such as myosin light chain kinase that related to protein kinase C or inhibition of calcium influx (De Rojas et al., 1999).
The dichloromethane extract of Ziziphora clinopodioides Lam. (ZDCE) had shown a significant effect on the inhibition of extracellular Ca 2+ induced contraction in the pre-contracted rings by high KCl and phenylephrine. It also caused an inhibition of intracellular Ca 2+ release to the phenylephrine. Among the hexane, dichloromethane, and aqueous extracts, ZDCE had shown the endothelium-independent vasodilation properties that occurs due to the extracellular Ca 2+ influx via the voltage and receptor-operated Ca 2+ channels, causing Ca 2+ inhibition from the stores of the intracellular and lastly via opening the K + channels which are voltage-dependent (Senejoux et al., 2010).

Anticoagulation and Anti-Thrombosis Activity
A series of zymogens are involved in the blood coagulation process. Proteolysis caused the conversion of zymogens into active enzymes that caused the production of thrombin, which can lead to the conversion of fibrinogen into fibrin (Rand et al., 1996). Enzymes are involved in mediating the blood coagulation of damaged tissues. Factor VII (FVII) binds to uncovered tissue factor (TF), which triggers the development of thrombin that causes coagulation of blood. Anticoagulant inhibits thrombin generation and fibrin formation. An ideal clinical anticoagulant should inhibit thrombin activity without induced bleeding. Erigeron canadensis L. consists of different types of flavonoids and tannins on top of the essential oil that is present. Its polyphenolic-polysaccharide preparation was isolated from its flowering part and was determined its anticoagulant activity via in vivo assay (Pawlaczyk et al., 2011). The plant preparation had shown its anti-platelet activity specifically towards the cyclooxygenase pathway that was induced by the arachidonic acid (AA), which is similar to acetylsalicylic acid activity. The assay was conducted on standardized human plasma by measuring prothrombin time (PT) and partial thromboplastin time (aPTT). The plant preparation inhibited plasma clot formation in aPTT and PT at the concentration of 390 µg/mL and 1.56 mg/mL, respectively. The plant preparation also exhibited significant anti-IIa activity mediated by the cofactor II of heparin. Further fractionation of the plant preparation at the concentration of 50 µg/mL, showed higher anticoagulation activity in aPTT test corresponded to 7 to 9 IU/mg of 5 th International Standard for Unfractionated Heparin (ISUH). In vivo studies also showed that the dose of 50 mg/mL of the plant preparation has the anticoagulant effect in the rat. These anticoagulant activities are essential in patients suffering from deep vein thrombosis, and those had already been resistant to the acetylsalicylic derivatives drugs (Pawlaczyk et al., 2011).
Marrubiin (20) was isolated from Leonotis leonurus (L.) R. Br., and both were tested via in vivo and in vitro studies to determine their anticoagulation reaction (Mnonopi et al., 2011). The marrubiin (20) and the plant extract suppressed the inflammatory markers, platelet aggregation, and coagulation marker while prolonged aPTT. The extract and marrubiin (20) in the concentration of 100 µg/mL were administered on rats. It was observed that the platelet adhesion was reduced in a dosedependent manner, together with a depletion in protein secretion, fibrin formation, and d-dimer. The intracellular levels of Ca 2+ were also reduced in a concentration-dependent manner and inhibited the calcium mobilization that was induced by thrombin by 50 to 200 µg/mL. This study shows that marrubiin (20) and the extract may have a direct inhibitory effect upon the synthase activity of cyclooxygenase or thromboxane due to the suppression of thromboxane B2 production (Mnonopi et al., 2011).
Leuzea carthamoides Willd. DC. consists of eriodictyol (21) and patuletin (22), which have similar antiplatelet activity (Koleckar et al., 2008). The leaf parts of the plant exhibited antiplatelet activity by inhibiting arachidonic acid and collageninduced platelet aggregation. It showed a more potent antiplatelet activity in the collagen-induced aggregation compared to the arachidonic acid-induced aggregation. The mechanism that was exhibited by eriodictyol (21) is the decrease in antiplatelet potency that was caused by glucosylation process. Based on the study, apigenin and quercetin formed from the glycosylation process exhibited a lesser activity compared to their aglycons (Guerrero et al., 2005). Based on the study, the extract of the L. carthamoides has a potent antithrombotic effect due to the presence of the antithrombotic agents, not due to the effect of the specific flavonoids that are present in the extract. The plant had shown a strong inhibition activity upon the platelet aggregation that was induced by adenosine diphosphate (ADP) (Koleckar et al., 2008).
Salvia miltiorrhiza Bunge consists of phenolic acid that is water-soluble, which is the salvianolic acid (23) (SAA). The study examined the effect of SAA in the antiplatelet and antithrombotic effect (Fan et al., 2010). In the in vitro assay, Tyrode's solution was used to study the antiplatelet properties using a platelet aggregometer. The maximum height reached via the aggregation curves determines the extent of platelet aggregation of SAA. All tests showed that SAA had an inhibitory effect on ADP, thrombin, and platelet aggregation that was induced by AA. The compound inhibited ADP-induced platelet aggregation of rats with an IC 50 value of 390 µg/mL, whereby it inhibited the thrombin-induced platelet aggregation with an IC 50 value of 912 µg/mL. SAA (1,000 µg/mL) exhibited mild inhibitory activity on AA-induced platelet aggregation. In the in vivo study, the administration of SAA at dose 2.5, 5, and 10 mg/kg via intravenous caused dose-dependent inhibition upon the platelet aggregation in the rats. A similar observation with the in vitro study was observed. This study claimed that the SAA antiplatelet activity was due to the interference to a common signaling pathway, then directly binding to thrombin, ADP or AA to their respective receptors. The inhibition of ADP from dense granules of activated platelet might be one of the factors of the anti-aggregating properties of SAA (Fan et al., 2010).
The anticoagulant activity of Tridax procumbens (L.) L. was examined (Naqash and Nazeer, 2011). Sulfated polysaccharide isolated from the leaf extract of T. procumbens acts as an anticoagulant on heparin and chondroitin sulfate. Based on the in vivo assay, the activated aPTT had been prolonged to 113 s at 100 mg/mL by the sulfated polysaccharides from T. procumbens, which is almost 4-fold higher than the standard group. The sulfate group causes the anticoagulant activity but it is dependent on the sulfate group position in the chemical structure (Naqash and Nazeer, 2011).

Diuresis Action
Diuresis is an important mode of treatment for cardiovascular diseases, such as hypertension. It can increase the urinary volume and has a fewer side effect compared to others. Diuretics usually used as an independent drug or a combination with other drugs of the same mechanism of action in easing various conditions such as congestive heart failure, ascites, and pulmonary edema as well. Thus, few of the available diuretics cause adverse effects such as an imbalance of electrolytes, alterations in metabolic status, and some may impair the sexual function (Gupta and Neyses, 2005;Morganti, 2005).
Based on the previous studies of Asteraceae and Lamiaceae plant species, the number of plant species that exhibits diuretic effects is lesser than those other mechanisms, such as antioxidants, antihyperlipidemic, and vasorelaxant. The plant species that possess diuretic effect from the Asteraceae family are Chamaemelum nobile (L.) All., Chrysanthemum x morifolium Ramat. Hemsl., and Tanacetum vulgare L. and the plant species from Lamiaceae family are Ajuga integrifolia Buch.-Ham. ex D. Don (syn. Ajuga remota Benth.), Anisomeles indica (L.) Kuntze, and Plectranthus amboinicus (Lour) Spreng. The diuretic effect of C. nobile was assessed by examining the rats' urine after fasted overnight (Zeggwagh et al., 2009). After repeated oral administration of 140 mg/kg aqueous plant extract for three weeks, the extract showed a diuretic and hypotensive effect.
Plectranthus amboinicus (Lour) Spreng is a plant species from the Lamiaceae family. Its leaf aqueous, alcoholic, and ethyl acetate extracts increased urine volume and decreased serum sodium level of albino rats after 24 h compared to the moduretic drug (El-Hawary et al., 2012). Meanwhile, the extracts did not show any significant effect on the rats' potassium level. Based on the study, the ethyl acetate fraction was more potent as a diuretic group with better electrolyte balance (El-Hawary et al., 2012).
Tanacetum vulgare L. leaf extract was studied on its ability to act as a diuretic on rats (Lahlou et al., 2007). Water extract of the plant at a dose of 100 mg/kg was administered orally to the male Wistar rats. An increase in urine output was identified after 24 h of administration of the extract with a similar amount compared to furosemide administration. The extract had caused an increased level of Na + and K + in the urine, compared to furosemide, which has only an increase in Na + . In contrast, the extract does not affect Na + and K + levels of the plasma. The diuretic effect occurs due to the renal tubular suppression upon its tendency for reabsorption of electrolytes and water into the bloodstream. The plant extract does not cause any renal toxicity as repeated dosing upon the rat for nine consecutive days. Thus, it requires a clinical study to ensure that its safety profile matches up with the physiology of humans and the long duration that patients usually take on diuretics. Different studies have shown that T. vulgare consists of flavonoids, tri-and sesquiterpene lactones and isoprenoids, polysaccharides, saponins, and polyphenols. Thus, it is unsure of which compound contributes to the diuretic effect of this extract (Lahlou et al., 2007).

TOXICOLOGICAL STUDIES
There are plenty of pharmacological studies on the Asteraceae and Lamiaceae plant species on its cardiovascular effects, while the toxicological aspects of these species have yet to be explored. Most of the people believe that medicines that are from medicinal plants or herbal medicines are always safe, simply due to the belief that all plants are safe to be consumed. This does not apply to all the medicinal plants. Medicinal plants have their toxicity nature depending on their dosage and method of extraction (Chanda et al., 2015).
Based on the studies in this review, few had included its toxicology test results and had herbal drug interaction during the administration of the medicinal plant extract in specific conditions. Traditional preparation methods of the medicinal plants into a consumable substance take different toxicity levels. The level of toxicity differs according to the solvents used. Thus it is important to choose the appropriate solvent either for in vivo or in vitro experiments.
Acute toxicity test of Artemisia campestris L. showed no symptoms of toxicity upon its aqueous extract administration of doses 1, 2, 4, and 6 g/kg (Dib et al., 2017).Based on the acute toxicological studies on C. crepidioides (Benth.) S. Moore, it showed that consumption of the plant extract at a dose of 2500 mg/kg was safe. During the observation on the first 8 h, within the interval of every 8 h and upon the next 72 h, no significant change in the animal behavior or mortality was observed (Bahar et al., 2016). It showed that the dose is safe in the in vivo testing.
Acute toxicity study was conducted on the ethanolic extract of Launaea intybacea (Jacq.) Beauverd (syn. Lactuca runcinata DC.) in 1% gum acacia upon rats (Devi and Muthu, 2015). Subsequent administration of the extract at dose 2,000 mg/kg body weight of rats for 14 days showed no toxicity effect, and this dose had helped in the reduction of total cholesterol and elevated the HDL level.
The plant in this study that showed toxicity is Leonurus cardiaca L. Lavandulifolioside, the active component of L. cardiaca, showed moderate toxicity at the amount of 1,000 mg/ kg on the LD 50 when given intravenously (Wojtyniak et al., 2013). The butanol extract of the plant showed higher toxicity with LD 50 of 400 mg/kg when administered intravenously compared to LD 50 of 2,000 mg/kg when administered orally. This showed that the intake of this drug via intravenous possess a higher toxicity possibility than via oral intake (Wojtyniak et al., 2013).
Aqueous extract of Salvia scutellarioides Kunth was administered on mice in two doses of 1 or 2 g/kg for 28 days (Ramirez et al., 2007). The administration showed no mortality. The study also claimed that if S. scutellarioides is taken together with other diuretics drug, it might worsen hypokalemia symptoms or increase in digoxin related arrhythmias in patients because of the herb-drug interactions. (Ramirez et al., 2007). Teucrium polium L. is known for its risk of hepatotoxicity due to hepatocyte necrosis occurs massively in the central lobular area such as lymphocyte inflammatory inflate, bile duct proliferation, and bile retention. Clinical signs are often seen in the usage of this plant; thus, proper usage of this plant on the therapeutic range would resolve the problem.

CONCLUSION
The last few decades have witnessed several rapid changes in the traditional use of the medicinal plant in developing countries.
However, some of the traditional use of the medicinal plant is undocumented that results in the decline of knowledge and making it unreliable. Therefore, it has become necessary to document the knowledge and shared them entirely to ensure their quality and preservation. Based on this review, medicinal plants were widely consumed using decoction or taken orally as a raw product of fruits, leaves, and roots. Most of the plants from Asteraceae and Lamiaceae family are rich in flavonoids and terpenoids, together with other phytochemicals that act as the inducer of the mechanism in alleviating cardiovascular diseases. The plants have a strong antioxidant effect, followed by antihyperlipidemic, vasodilation, antithrombotic, and diuretic effects which are mechanisms that are closely related in resolving cardiovascular diseases such as coronary heart diseases (CHD), atherosclerosis, hypertension, and others. As the medicinal plant being beneficial for treating human ailments, we should not waste these resources by leaving them to grow wild and perish, without utilizing them for better pharmaceutical development in the future.

FUTURE STUDIES
Based on the evidence-based review on the use of medicinal plant from the plant family of Asteraceae and Lamiaceae in cardiovascular diseases, we hope that information from this review will facilitate future research initiatives to develop new medicinal plant-based medication for cardiovascular disease treatment or continue with any clinical studies to prove the effectiveness of this medicinal plant upon humans. The clinical trial needs to be performed to have a better knowledge of their safety and efficacy to ensure that it can be beneficial to the human race.

AUTHOR CONTRIBUTIONS
JM obtained the pieces of literature and wrote the manuscript while NA and KH edited the manuscript.