Hypercholesterolemia links hematopoiesis with atherosclerosis

doi:10.1016/j.tem.2012.10.008

Trends in Endocrinology & Metabolism

Volume 24, Issue 3, March 2013, Pages 129-136

https://doi.org/10.1016/j.tem.2012.10.008 Get rights and content

Atherosclerosis is characterized by the progressive accumulation of lipids and leukocytes in the arterial wall. Leukocytes such as macrophages accumulate oxidized lipoproteins in the growing atheromata and give rise to foam cells, which can then contribute to the necrotic core of lesions. Lipids and leukocytes also interact in other important ways. In experimental models, systemic hypercholesterolemia is associated with severe neutrophilia and monocytosis. Recent evidence indicates that cholesterol-sensing pathways control the proliferation of hematopoietic stem-cell progenitors. Here we review some of the studies that are forging this particular link between metabolism and inflammation, and propose several strategies that could target this axis for the treatment of cardiovascular disease.

Section snippets

Hypercholesterolemia and inflammation orchestrate atherosclerosis

Atherosclerosis is a chronic disease of the vascular wall and a primary cause of myocardial infarction, stroke, and peripheral vascular disease 1, 2. It has been understood for a long time that atherosclerosis involves the progressive accumulation of lipids in the vascular wall. Numerous experimental and epidemiological studies have linked hypercholesterolemia and high serum levels of low-density lipoprotein (LDL) to the development of atherosclerosis and its complications 3, 4. Randomized

Hypercholesterolemia-induced monocytosis and neutrophilia promote atherosclerosis

Already in the 1970s it was noticed that peripheral leukocyte counts may predict future cardiovascular events [16]. Subsequent association studies focusing on circulating neutrophil and monocyte counts and cardiovascular risk correlated leukocytes with the risk for a cardiovascular event 17, 18, 19. In mouse models of atherosclerosis, counts of circulating Ly-6C^high monocytes 13, 20, 21 and neutrophils 22, 23 correlate with atherosclerotic lesion burden. Human studies have further shown that

Hypercholesterolemia induces proliferation of hematopoietic stem and progenitor cells (HSPC)

Intracellular cholesterol homeostasis is regulated by the ATP-binding cassette transporter ABCA1, which transports cholesterol from membranes to nascent HDL, and the ATP-binding cassette sub-family G member 1, ABCG1, which transports cholesterol to mature HDL. Deletion of these cholesterol efflux transporters leads to leukocytosis and exaggerated atherogenesis 36, 37. Mechanistically, Yvan-Charvet et al. found that leukocytosis in Abca1^−/−Abcg1^−/− mice is primarily mediated by increased

LXR signaling links lipid metabolism with inflammation

Liver X receptors (LXRα and LXRβ) are members of the nuclear family of transcription factors that regulate cellular cholesterol efflux [42]. The natural ligands for LXRs are oxysterols and intermediates in the cholesterol biosynthetic pathway [43]. LXRs regulate the expression of genes involved in cholesterol metabolism; the net effect of LXR activation is to promote the directional movement of excess cholesterol from peripheral tissues to the liver, bile, and intestinal lumen, for excretion

Hypercholesterolemia induces HSPC mobilization and extramedullary hematopoiesis

Monocytes and neutrophils arise in the bone marrow in the steady-state from hematopoietic stem cells residing in specialized locations, or niches. Cellular self-renewal, differentiation, survival, and mobilization are tightly controlled processes that rely on a diverse repertoire of cells and molecules necessary to ensure continuous leukocyte replenishment throughout life 56, 57. In experimental models of atherosclerosis, however, substantial extramedullary hematopoiesis occurs in secondary

Novel approaches for treatment of atherosclerosis

Recent advances at the intersection of lipid metabolism and cellular homeostasis have revealed possible new therapeutic targets for atherosclerosis. Interference with leukocyte accumulation in atherosclerosis has previously focused on inhibition of leukocyte recruitment into large arteries 64, 65. However, targeting of cell-adhesion molecules has so far been largely unsuccessful 65, 66, 67. Reasons for such failures include the striking redundancy of cell-adhesion molecules and chemokines

Concluding remarks

Atherosclerosis is a chronic inflammatory disease of the arterial wall involving the accumulation of myeloid cells as a hallmark event. Recent work has revealed multiple mechanisms by which atherosclerotic lesions grow. Endothelial expression of cell-adhesion molecules and chemokines controlling leukocyte influx is one major determinant of atherosclerosis. Mechanisms regulating myeloid cell production in the bone marrow and secondary lymphoid organs such as the spleen, myeloid cell

Acknowledgments

O.S. was supported by the German Research Foundation (SO876/3-1, FOR809, SFB914 TPB08), the German-Israeli Foundation, the FöFoLe Program within the Medical Faculty of the LMU Munich, the Else Kröner Fresenius Stiftung, and the NWO. F.K.S. was supported by the National Institutes of Health (R01 HL095612).

Glossary

Atheromata: also termed atheromatous plaques, an accumulation of macrophage cells, cholesterol, and fatty acids and fibrous connective tissue in artery walls.
Chemokines: a family of small cytokines, or proteins secreted by cells. They exert their biological effects by interacting with G protein-linked transmembrane receptors known as chemokine receptors found on the surfaces of their target cells, thereby regulating directed movement of cells.
Chemokine receptors: 7-transmembrane structure G

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Dendritic cells (DCs), professional antigen-presenting cells, play an important role in pathologies by controlling adaptive immune responses. However, their adaptation to and functionality in hypercholesterolemia, a driving factor in disease onset and progression of atherosclerosis remains to be established.
In this study, we addressed the immediate impact of high fat diet-induced hypercholesterolemia in low-density lipoprotein receptor deficient (Ldlr^−/−) mice on separate DC subsets, their compartmentalization and functionality.
While hypercholesterolemia induced a significant rise in bone marrow myeloid and dendritic cell progenitor (MDP) frequency and proliferation rate after high fat diet feeding, it did not affect DC subset numbers in lymphoid tissue. Hypercholesterolemia led to almost immediate and persistent augmentation in granularity of conventional DCs (cDCs), in particular cDC2, reflecting progressive lipid accumulation by these subsets. Plasmacytoid DCs were only marginally and transiently affected. Lipid loading increased co-stimulatory molecule expression and ROS accumulation by cDC2. Despite this hyperactivation, lipid-laden cDC2 displayed a profoundly reduced capacity to stimulate naïve CD4⁺ T cells.
Our data provide evidence that in hypercholesterolemic conditions, peripheral cDC2 subsets engulf lipids in situ, leading to a more activated status characterized by cellular ROS accumulation while, paradoxically, compromising their T cell priming ability. These findings will have repercussions not only for lipid driven cardiometabolic disorders like atherosclerosis, but also for adaptive immune responses to pathogens and/or endogenous (neo) antigens under conditions of hyperlipidemia.
Single-cell and bulk RNA-sequencing analysis to predict the role and clinical value of CD36 in lung squamous cell carcinoma
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The majority of patients with lung squamous cell carcinoma are diagnosed at an advanced stage, which poses a challenge to the efficacy of chemotherapy. Therefore, the search for an early biomarker needs to be addressed. CD36 is a scavenger receptor expressed in various cell types. It has been reported that it is closely related to the occurrence and development of many kinds of tumours. However, its role in lung squamous cell carcinoma has not been reported. Our research aims to reveal the role of CD36 in lung squamous cell carcinoma by integrating single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data. We used bioinformatics methods to explore the potential carcinogenicity of CD36 by analysing the data from the cancer genome map (TCGA), gene expression comprehensive map (GEO), human protein map (HPA) comparative toxicology genomics database (CTD) and other resources. Our study dissected the relationship between CD36 and prognosis and gene correlation, functional analysis, mutation of different tumours, infiltration of immune cells and exploring the interaction between CD36 and chemicals. The results showed that the expression of CD36 was heterogeneous. Compared with normal patients, the expression was low in lung squamous cell carcinoma. In addition, CD36 showed early diagnostic value in four kinds of tumours (LUSC, BLCA, BRCA and KIRC) and was positively or negatively correlated with the prognosis of different tumours. The relationship between CD36 and the tumour immune microenvironment was revealed by immunoinfiltration analysis, and many drugs that might target CD36 were identified by the comparative toxicological genomics database (CTD). In summary, through pancancer analysis, we found and verified for the first time that CD36 may play a role in the detection of lung squamous cell carcinoma. In addition, it has high specificity and sensitivity in detecting cancer. Therefore, CD36 can be used as an auxiliary index for early tumour diagnosis and a prognostic marker for lung squamous cell carcinoma.
Elevated White Blood Cell Count Resultant Atherogenesis is Associated With Panoramic-Imaged Carotid Plaque
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Atherosclerotic plaques develop as a result of a low-grade, chronic, systemic inflammatory response to the injury of endothelial cells arising from lipid deposition within the intima. Increased white blood cell count (WBCC) is both a validated “biologic marker” of the extent of this inflammatory process and a key participant in the development of subsequent atherosclerotic ischemic heart disease manifesting as myocardial infarction. We sought to determine if calcified carotid artery plaque (CCAP) on a panoramic image (PI), also a validated risk indicator of future myocardial infarction, is associated with increased WBCC.
We retrospectively evaluated the PI and medical records of White male military veterans aged 55 years and older treated by a VA dental service. Established were 2 cohorts of patients, 50 having plaques (CCAP+) and 50 without plaques (CCAP−). Predictor variable was CCAP+; outcome variable was WBCC. Bootstrapping analysis determined the differences in mean WBCCs between groups. Statistical significance set at ≤ 0.05.
The study group, (mean age 74; range 59 to 91 years) demonstrated a mean WBCC of 8,062 per mm³. The control group, (mean age 72 range; 57 to 94) evidenced a mean WBCC of 7,058 per mm³. Bootstrapping analysis of WBCC values demonstrated a significant (P = .012) difference (95% confidence interval of difference of mean, −806, 742; observed effect size, 1004) between groups.
The presence of CCAP demonstrated on PIs of older Caucasian men is associated with elevated WBCC. Concomitant presence of CCAP on PI and increased WBCC (≥7,800 per mm³) amplifies need for medical consultation before intravenous anesthesia and maxillofacial surgical procedures.
The association of serum lipid and lipoprotein levels with total and differential leukocyte counts: Results of a cross-sectional and longitudinal analysis of the UK Biobank
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Citation Excerpt :
However, the precise interaction between leukocyte counts and CVD remains ill-defined. Results of preclinical studies suggest that lipids are directly involved in leukogenesis [10]. Hypercholesterolemia in mice induces monocytosis, neutrophilia and mobilisation of hematopoietic stem cells (HSC) from the bone marrow into the peripheral circulation, likely via disruption of the stromal cell-derived factor-1:chemokine receptor 4 axis [11–13].
There is some evidence of a cross-sectional, and possibly causal, relationship of lipid levels with leukocyte counts in mice and humans. This study investigates the cross-sectional and longitudinal relationship of blood lipid and lipoprotein levels with leukocyte counts in the UK Biobank cohort.
The primary cross-sectional analysis included 417,132 participants with valid data on lipid measures and leukocyte counts. A subgroup analysis was performed in 333,668 participants with valid data on lipoprotein(a). The longitudinal analysis included 9058 participants with valid baseline and follow-up data on lipid and lipoprotein levels and leukocyte counts. The association of lipid and lipoprotein levels with leukocyte counts was analysed by multivariable linear regression.
Several relationships were significant in both cross-sectional and longitudinal analysis. After adjustment for demographic, socioeconomic and other confounding factors, a higher eosinophil count was associated with lower HDL cholesterol and apolipoprotein A-I concentration (p < 0.001). Higher triglycerides levels were associated with higher total leukocyte, basophil, eosinophil, monocyte and neutrophil counts (all p < 0.01). A higher lymphocyte count was associated with a higher apolipoprotein B level (p < 0.001). In the longitudinal analysis, lipoprotein(a) was inversely associated with basophil count in men but not women (p < 0.001).
Triglyceride levels demonstrate a robust positive association with total and differential leukocyte counts suggesting they may be directly involved in leukogenesis. However, unlike in murine models, the remainder of these relationships is modest, which suggests that cholesterol and lipoproteins are minimally involved in leukogenesis in humans.
Advanced atherosclerotic plaques in animal models versus human lesions: Key elements to translation
2021, Biomechanics of Coronary Atherosclerotic Plaque: From Model to Patient
Animal models have been extensively used to understand atherogenesis and the complex biological mechanisms of atherosclerosis. Yet, their advanced plaque morphologies may have distinct features from human coronary lesions and strikingly, they often do not lead to acute cardiac events, at least in mice models. These particularities will be presented in the major models of advanced plaques together with their respective specific localizations. Next, in light of recent major translational advances regarding the role of inflammation in plaque vulnerability, the main findings from animal models to human applications will be given, opening new diagnoses and therapeutic targets. Finally, biomechanics has mainly been evaluated in human plaques, but differences and similarities between animal models and human lesions shed new light on prediction markers of acute events.
The APOA1bp–SREBF–NOTCH axis is associated with reduced atherosclerosis risk in morbidly obese patients
2020, Clinical Nutrition
Atherosclerosis is characterized by an inflammatory disease linked to excessive lipid accumulation in the artery wall. The Notch signalling pathway has been shown to play a key regulatory role in the regulation of inflammation. Recently, in vitro and pre-clinical studies have shown that apolipoprotein A–I binding protein (AIBP) regulates cholesterol metabolism (SREBP) and NOTCH signalling (haematopoiesis) and may be protective against atherosclerosis, but the evidence in humans is scarce.
We evaluated the APOA1bp–SREBF–NOTCH axis in association with atherosclerosis in two well-characterized cohorts of morbidly obese patients (n = 78) within the FLORINASH study, including liver transcriptomics, ¹H NMR plasma metabolomics, high-resolution ultrasonography evaluating carotid intima-media thickness (cIMT), and haematological parameters.
The liver expression levels of APOA1bp were associated with lower cIMT and leukocyte counts, a better plasma lipid profile and higher circulating levels of metabolites associated with lower risk of atherosclerosis (glycine, histidine and asparagine). Conversely, liver SREBF and NOTCH mRNAs were positively associated with atherosclerosis, liver steatosis, an unfavourable lipid profile, higher leukocytes and increased levels of metabolites linked to inflammation and CVD such as branched-chain amino acids and glycoproteins. APOA1bp and NOTCH signalling also had a strong association, as revealed by the negative correlations among APOA1bp expression levels and those of all NOTCH receptors and jagged ligands.
We here provide the first evidence in human liver of the putative APOA1bp–SREBF–NOTCH axis signalling pathway and its association with atherosclerosis and inflammation.

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Trends in Endocrinology & Metabolism

ReviewHypercholesterolemia links hematopoiesis with atherosclerosis

Section snippets

Hypercholesterolemia and inflammation orchestrate atherosclerosis

Hypercholesterolemia-induced monocytosis and neutrophilia promote atherosclerosis

Hypercholesterolemia induces proliferation of hematopoietic stem and progenitor cells (HSPC)

LXR signaling links lipid metabolism with inflammation

Hypercholesterolemia induces HSPC mobilization and extramedullary hematopoiesis

Novel approaches for treatment of atherosclerosis

Concluding remarks

Acknowledgments

Glossary

Comp. Biochem. Physiol. B.

Immunity

Blood

Am. J. Cardiol.

Immunity

Immunity

J. Biol. Chem.

Immunity

J. Biol. Chem.

Immunity

Cell Stem Cell

Immunity

Trends Pharmacol. Sci.

J. Lipid Res.

J. Biol. Chem.

Lancet

Am. J. Pathol.

Atherosclerosis

Atherosclerosis

Atherosclerosis

Atherosclerosis

Blood

Translating molecular discoveries into new therapies for atherosclerosis

Nature

Inflammation, atherosclerosis, and coronary artery disease

N. Engl. J. Med.

Cholesterol–phospholipid ratio in the prediction of coronary heart disease. The Framingham study

N. Engl. J. Med.

Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study

N. Engl. J. Med.

Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease

N. Engl. J. Med.

Lifestyle, serum lipids and coronary artery disease: comparison of Japan with the United States

J. Atheroscler. Thromb.

Atherosclerosis – an inflammatory disease

N. Engl. J. Med.

Atherosclerosis: current pathogenesis and therapeutic options

Nat. Med.

Multiple roles for neutrophils in atherosclerosis

Circ. Res.

Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata

J. Clin. Invest.

Progress and challenges in translating the biology of atherosclerosis

Nature

Functional alterations of myeloid cell subsets in hyperlipidaemia: relevance for atherosclerosis

J. Cell. Mol. Med.

The leukocyte count as a predictor of myocardial infarction

N. Engl. J. Med.

Monocyte count: a risk factor for coronary heart disease?

Am. J. Epidemiol.

Total and differential leukocyte counts as predictors of ischemic heart disease: the Caerphilly and Speedwell studies

Am. J. Epidemiol.

Neutrophils and clinical outcomes in patients with acute coronary syndromes and/or cardiac revascularisation. A systematic review on more than 34,000 subjects

Thromb. Haemost.

Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques

J. Clin. Invest.

Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice

Circulation

Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis

Circulation

Hematopoietic interferon regulatory factor 8-deficiency accelerates atherosclerosis in mice

Arterioscler. Thromb. Vasc. Biol.

Peripheral blood mononuclear phagocyte subpopulations as cellular markers in hypercholesterolemia

Arterioscler. Thromb. Vasc. Biol.

CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow

J. Clin. Invest.

Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters

Int. J. Obes.

Review
Hypercholesterolemia links hematopoiesis with atherosclerosis

Decreased lesion formation in CCR2^−/− mice reveals a role for chemokines in the initiation of atherosclerosis