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.
Highlights
We focus on how hypercholesterolemia speeds up the development of atherosclerosis
This study elaborately demonstrated the timing and dynamics of different leukocyte subsets rolling to carotid bifurcation: (1) myeloid cells started to adhere to the carotid bifurcation after 10 days of high-fat diet (HFD); (2) the number of rolling neutrophils increased over time after two and six weeks of HFD, whereas monocytes number remained similar as both time points, but decreased after six weeks of HFD; and (3) T lymphocytes started rolling after six weeks of HFD
In line with these reports, hypercholesterolemia is tightly associated with monocytosis and neutrophila [46], whereas Statins inhibits hypercholesterolemia-induced leukocytosis and reduces the amount of atherogenic inflammatory cells [46]
Summary
Endothelial cells in arteries are exposed to unsteady flow because the velocity of blood waves during cardiac cycle. This study elaborately demonstrated the timing and dynamics of different leukocyte subsets rolling to carotid bifurcation: (1) myeloid cells started to adhere to the carotid bifurcation after 10 days of high-fat diet (HFD); (2) the number of rolling neutrophils increased over time after two and six weeks of HFD, whereas monocytes number remained similar as both time points, but decreased after six weeks of HFD; and (3) T lymphocytes started rolling after six weeks of HFD They found that activated platelets were adhered to the plaque via interaction of previously-tethered monocytes and neutrophils [25]. When looking for insight into differential white blood cell counts, circulating monocytes and neutrophils are positively associated with the occurrence and progression of CVD [44,45] In line with these reports, hypercholesterolemia is tightly associated with monocytosis and neutrophila [46], whereas Statins inhibits hypercholesterolemia-induced leukocytosis and reduces the amount of atherogenic inflammatory cells [46]. These resident HSPC have been proven to differentiate into lymphocytes for immune surveillance [78]
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