Regulation of High-Density Lipoprotein on Hematopoietic Stem/Progenitor Cells in Atherosclerosis Requires Scavenger Receptor Type BI Expression

Objective-Recently, we demonstrated that scavenger receptor type BI (SR-BI), a high-density lipoprotein (HDL) receptor, was expressed on murine hematopoietic stem/progenitor cells (HSPC) and infusion of reconstituted HDL and purified human apolipoprotein A-I (apoA-I) suppressed HSPC proliferation. We hypothesized that SR-B1 expression is required for the observed antiproliferative effects of HDL on HSPC. Approach and Results-SR-BI-deficient (SR-BI-/-) mice and wild-type controls were fed on chow or high-fat diet (HFD) for 8 to 10 weeks. Under chow diet, a significant increase in Lin(-) Sca1(+) cKit(+) cells (LSK cells, so-called HSPC) was found in the bone marrow of SR-BI-/- mice when compared with wild-type mice. HFD induced a further expansion of CD150(+)CD48(-) LSK cells (HSC), HSPC, and granulocyte monocyte progenitors in SR-BI-/- mice. Injection of reactive oxygen species inhibitor N-acetylcysteine attenuated HFD-induced HSPC expansion, leukocytosis, and atherosclerosis in SR-BI-/- mice. ApoA-I infusion inhibited HSPC cell proliferation, Akt phosphorylation and reactive oxygen species production in HSPC and plaque progression in low-density lipoprotein receptor knockout (LDLr-/-) apoA-I-/- mice on HFD but had no effect on SR-BI-/- mice on HFD. Transplantation of SR-BI-/- bone marrow cells into irradiated LDLr-/- recipients resulted in enhanced white blood cells reconstitution, inflammatory cell production, and plaque development. In patients with coronary heart disease, HDL levels were negatively correlated with white blood cells count and HSPC frequency in the peripheral blood. By flow cytometry, SR-BI expression was detected on human HSPC. Conclusions-SR-BI plays a critical role in the HDL-mediated regulation HSPC proliferation and differentiation, which is associated with atherosclerosis progression.