TRPM2 deficiency in mice protects against atherosclerosis by inhibiting TRPM2–CD36 inflammatory axis in macrophages

Atherosclerosis is the major cause of ischemic heart disease and stroke, the leading causes of mortality worldwide. The central pathological features of atherosclerosis include macrophage infiltration and foam cell formation. However, the detailed mechanisms regulating these two processes are unclear. Here we show that oxidative stress-activated Ca²⁺-permeable transient receptor potential melastatin 2 (TRPM2) plays a critical role in atherogenesis. Both global and macrophage-specific Trpm2 deletions protect Apoe ^−/− mice against atherosclerosis. Trpm2 deficiency reduces oxidized low-density lipoprotein (oxLDL) uptake by macrophages, thereby minimizing macrophage infiltration, foam cell formation and inflammatory responses. Activation of the oxLDL receptor CD36 induces TRPM2 activity and vice versa. In cultured macrophages, TRPM2 is activated by the CD36 ligands oxLDL and thrombospondin-1 (TSP1); deleting Trpm2 or inhibiting TRPM2 activity suppresses the activation of the CD36 signaling cascade induced by oxLDL and TSP1. Our findings establish the TRPM2–CD36 axis as a molecular mechanism underlying atherogenesis and suggest TRPM2 as a potential therapeutic target for atherosclerosis.