Promoting macrophage survival delays progression of pre-existing atherosclerotic lesions through macrophage-derived apoE

Aims Macrophage apoptosis is a prominent feature of atherosclerosis, yet whether cell death-protected macrophages would favour the resolution of already established atherosclerotic lesions, and thus hold therapeutic potential, remains unknown. Methods and results We irradiated then transplanted into Apoe(-/-) or LDLr-/- recipient mice harbouring established atherosclerotic lesions, bone marrow cells from mice displaying enhanced macrophage survival through overexpression of the antiapoptotic gene hBcl-2 (Mo-hBcl2 Apoe(-/-) or Mo-hBcl2 Apoe(+/+) LDLr-/-). Both recipient mice exhibited decreased lesional apoptotic cell content and reduced necrotic areas when repopulated with Mo-hBcl2 mouse-derived bone marrow cells. In contrast, only LDLr-/- recipients showed a reduction in plasma cholesterol levels and in atherosclerotic lesions. The absence of significant reduction of plasma cholesterol levels in the context of apoE deficiency highlighted macrophage-derived apoE as key in both the regulation of plasma and tissue cholesterol levels and the progression of pre-existing lesion. Accordingly, hBcl2 expression in macrophages was associated with larger pools of Kupffer cells and Ly-6C(low) monocytes, both high producers of apoE. Additionally, increased Kupffer cells population was associated with improved clearance of apoptotic cells and modified lipoproteins. Conclusion Collectively, these data show that promoting macrophage survival provides a supplemental source of apoE, which hinders pre-existing plaque progression.