Abstract 602: High-Density Lipoprotein Protects Macrophages Against Apoptosis Through BH3-only Bcl-2 Family Member Bim

Macrophage apoptosis contributes to the formation of necrotic cores within atherosclerotic lesions, increasing the susceptibility of atherosclerotic plaques to rupture and the risk of cardiovascular events. In advanced atherosclerotic plaques, lipid-laden foam cells are exposed to a diverse number of apoptosis inducers, including prolonged endoplasmic reticulum (ER) stress. The pro-apoptotic BH3-only protein Bim has been reported to mediate apoptosis in response to ER stress induction in a variety of cells including macrophages. Treatment of macrophages with high-density lipoprotein (HDL) protects them against apoptosis induced by a variety of stressors. We hypothesize that HDL mediated protection against macrophage apoptosis occurs via pathways that regulate Bim activity. To test this, thioglycollate-elicted peritoneal macrophages were treated in lipoprotein deficient culture with different apoptosis inducers in the absence or presence of HDL. Cell apoptosis was assessed by cleaved caspase 3 staining and terminal deoxynucleotidal transferase dUTP nick end labeling. Treatment of mouse peritoneal macrophages in culture with 50μg/ml of human HDL protected against apoptosis induced by tunicamycin (P<0.05) without affecting ER stress markers, Grp78, Grp94 and CHOP. Peritoneal macrophages from mice deficient in Bim were less susceptible to apoptosis induced by treatment with either tunicamycin or 7-ketocholesterol. Furthermore, treatment with HDL provided no additional protection to apoptosis in Bim KO macrophages. Our results suggest that protection of macrophage apoptosis by HDL is regulated through pathways involving the activity of BH3-only Bcl-2 family member Bim.