LDL and HDL Counteract Hematopoietic Stem/Progenitor Cells in Regulation of Inflammation and Atherosclerosis

Abstract 1288

Low-density lipoprotein (LDL) is an independent risk factor in cardiovascular disease. Hypercholesterolemia-associated monocytosis and transformation of monocytes into macrophages are the main features underlying the proatherogenic property of LDL. Different from LDL, high-density lipoprotein (HDL) and its major apolipoprotein, apoA-I, counteract atherosclerosis by reversing cholesterol transport, inhibiting inflammatory cell adhesion to plaques, maintaining endothelial integrity, inhibiting oxidation, and as has recently been shown, suppressing hematopoietic stem cell (HSC) proliferation. As inflammatory cells in atherosclerotic plaques are exclusively derived from hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM), we hypothesized that differential effects of LDL and HDL on HSPC proliferation and differentiation may play a role in atherosclerotic plaque development. We explored the effect of HDL and LDL on HSPC number and function using LDL receptor knockout (LDLr ko) mice, fed with high fat diet, and C57BL/6 mice infused with purified apoA-I and or reconstituted (r)HDL. Compared to mice on normal diet, the number of lineage⁻/cKit⁺Sca-1⁺ (KLS) cells was 5-fold higher in LDLr ko mice on high-fat diet. By contrast, infusion of either 8 mg/kg apoA-I or 8, 12 and 16 mg/kg rHDL decreased the KLS cell frequency in BM. Using BrdU incorporation, we demonstrated that LDL induced but HDL inhibited KLS cell proliferation. When lineage negative cells, exposed to LDL or rHDL were used in competitive repopulation studies, HDL-treated cells supported greater chimerism than untreated controls, whereas LDL-treated cells competed less well. In addition, for HDL-treated Lin⁻ cells, skewing of reconstitution to the B-lymphoid lineage at the expense of the granulocyte/monocyte lineage was seen. In vitro, LDL promoted KLS cell differentiation towards the monocytic lineage, which was abrogated by addition of HDL. In conclusion, LDL and HDL have opposing effects on HSPC number and function. These differential effects may contribute to the opposing effects of HDL and LDL on atherosclerosis development.