Abstract 228: Trpm2 Deficiency In Macrophages Protects Mice Against Atherosclerosis

Abstract

Introduction: Atherosclerosis and its major complications, ischemic heart diseases and stroke, are the leading causes of mortality worldwide. The prominent feature of atherosclerosis is the formation of foam cells, the infiltrated macrophages overloaded with lipids. Lipid uptake by macrophages is mainly mediated by CD36. Hypothesis: Previously we reported that: (1) global Trpm2 deletion attenuates atherosclerosis; (2), TRPM2 and CD36 enhance the activation of each other in macrophages, thereby promoting foam cell formation. Thus, we hypothesized that macrophage specific Trpm2 deletion protects mice against atherosclerosis. Methods: Macrophage-specific Trpm2 deletion in was achieved by crossing Apoe -/- / Trpm2 fl/fl mice with Cd11b-cre mice. High-fat diet (HFD) was used to induce atherosclerosis, and total serum cholesterol level was measured. Oil Red O (ORO) staining was used to evaluate atherosclerotic lesion size. Immunofluorescence staining of Mac-1, F4/80 and CD80 was used to examine the macrophage content in the plaques, which was further confirmed by flow cytometry analysis of the immune cell populations in digested aortas. Inflammation of the aortas was examined by WB analysis of expression of NLRP3, ASC, Caspase-1, IL-1β, macrophage chemoattractant protein-1 (MCP1) and migration-inhibitory factor (MIF). Results: Macrophage-specific Trpm2 deletion: (1) did not influence the serum total cholesterol level; (2) decreased plaque lesion ratio as shown by en-face aorta ORO staining and reduced plaque size as shown by aortic root ORO staining; (3) reduced macrophage content and immune cell infiltration in the plaques; (4) inhibited NLRP3 inflammasome activation and inflammatory cytokines expression in the atherosclerotic aortas. Conclusion: Macrophage specific Trpm2 deletion attenuates HFD-induced atherosclerosis in Apoe -/- mice.