Hypercholesterolemia Tunes Hematopoietic Stem/Progenitor Cells for Inflammation and Atherosclerosis

Abstract

As the pathological basis of cardiovascular disease (CVD), atherosclerosis is featured as a chronic inflammation. Hypercholesterolemia is an independent risk factor for CVD. Accumulated studies have shown that hypercholesterolemia is associated with myeloid cell expansion, which stimulates innate and adaptive immune responses, strengthens inflammation, and accelerates atherosclerosis progression. Hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM) expresses a panel of lipoprotein receptors to control cholesterol homeostasis. Deficiency of these receptors abrogates cellular cholesterol efflux, resulting in HSPC proliferation and differentiation in hypercholesterolemic mice. Reduction of the cholesterol level in the lipid rafts by infusion of reconstituted high-density lipoprotein (HDL) or its major apolipoprotein, apoA-I, reverses hypercholesterolemia-induced HSPC expansion. Apart from impaired cholesterol metabolism, inhibition of reactive oxygen species production suppresses HSPC activation and leukocytosis. These data indicate that the mechanisms underlying the effects of hypercholesterolemia on HSPC proliferation and differentiation could be multifaceted. Furthermore, dyslipidemia also regulates HSPC-neighboring cells, resulting in HSPC mobilization. In the article, we review how hypercholesterolemia evokes HSPC activation and mobilization directly or via its modification of BM microenvironment. We hope this review will bring light to finding key molecules to control HSPC expansion, inflammation, and atherosclerosis for the treatment of CVD.

Dyslipidemic Diet-Induced Monocyte “Priming” and Dysfunction in Non-Human Primates Is Triggered by Elevated Plasma Cholesterol and Accompanied by Altered Histone Acetylation

“…Hypercholesterolemia has multiple effects on HSPCs, including (i) inducing HSPC proliferation and differentiation, (ii) mobilizing HSPCs for release from the bone marrow niche, and (iii) potentiating HSPCs for homing to extramedullary sites, including sites of tissue damage [reviewed in Ref. ( 35 , 36 )]. In rodent models of obesity, Nagareddy et al showed that obesity is associated with both monocytosis and neutrophilia.…”

Curcumin Inhibits Age-Related Vascular Changes in Aged Mice Fed a High-Fat Diet

“…It was revealed that aging and increased fat-derived energy intake are risk factors for arteriosclerotic disease, and enhanced oxidative stress and chronic inflammation are considered as the cause of arteriosclerotic disease [ 8 , 9 , 10 , 11 , 58 ]. Chronic inflammation is likely to develop in elderly people, and it was revealed that inflammatory cytokine levels in the blood are high even in healthy individuals [ 59 , 60 ].…”

“…This increase in fat-derived energy intake has been reported as a possible risk factor for arteriosclerotic disease [ 4 , 5 , 6 , 7 ]. Obesity and glycolipid metabolism disorder induced by this increased fat intake trigger oxidative stress characterized by increased reactive oxygen species and decreased anti-oxidative function as well as inflammatory reaction associated with abnormal secretions of adiponectin and inflammatory cytokines, which leads to the onset of arteriosclerotic disease [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Since preventing the onset and inhibiting the recurrence of arteriosclerotic disease are significant social challenges in Japan—a country with a super-aging society and an increasingly westernized diet—the expectations and efficacy of different functional foods on disease prevention and treatment have been actively studied [ 15 , 16 , 17 ].…”

Hematopoiesis is regulated by cholesterol efflux pathways and lipid rafts: connections with cardiovascular diseases

“…While LDL levels are correlated with circulating HSPCs, no correlation was observed with the white blood cell population. However, subjects in this study were either healthy or had only mild hypercholesterolemia, which may not necessarily lead to the typically observed increase in mature myeloid cells that occurs in familial hypercholesterolemia (FH) patients, who have 2-3-fold higher LDL-C levels (23,93). It appears paradoxical that high LDL-C content activates Srebp2 in circulating HSPCs.…”