Apolipoprotein A1 deficiency increases macrophage apoptosis and necrotic core development in atherosclerotic plaques in a Bim-dependent manner

In advanced atherosclerotic lesions, macrophage apoptosis contributes to plaque progression and the formation of necrotic cores, rendering plaques vulnerable to rupture. The proapoptotic protein B-cell lymphoma 2 [Bcl-2] interacting mediator of cell death (Bim) plays a crucial role in mediating apoptosis in macrophages under prolonged endoplasmic reticulum stress. HDL has been shown to suppress macrophage apoptosis induced by endoplasmic reticulum stressors. To investigate the impact of apolipoprotein A1 (ApoA1) deficiency, associated with reduced HDL levels, on necrotic core growth and plaque apoptosis, we introduced ApoA1 deficiency into low-density lipoprotein receptor (LDLR) knockout mice and fed them a high-fat diet for 10 weeks. ApoA1-deficient Ldlr KO mice developed advanced plaques characterized by large necrotic cores, increased apoptosis, and elevated Bim expression in macrophages within the plaques. To assess whether deletion of Bim could mitigate this development, mice underwent bone marrow transplantation with bone marrow from either Bim-deficient mice or from mice with a deletion of myeloid-derived Bim driven by LyzM-cre. Inhibiting Bim in all bone marrow-derived cells led to leukocytosis, reductions in plasma cholesterol and triglyceride levels, and decreased plaque apoptosis, necrotic core, and plaque sizes in ApoA1 and Ldlr double-KO mice but not in Ldlr KO mice. Likewise, conditional deletion of Bim in the myeloid compartment of ApoA1 and Ldlr double-KO mice also reduced apoptosis, necrotic core sizes, and plaque sizes, without inducing leukocytosis or lowering plasma cholesterol levels. These findings suggest that ApoA1 deficiency triggers apoptosis in myeloid cells through a Bim-dependent pathway, significantly contributing to the development of necrotic cores and the progression of atherosclerotic plaques.