Abstract 11314: Trpm2Deletion Alleviates Atherosclerosis by Inhibiting the Activation of CD36 in Macrophages

Introduction:Atherosclerosis and its complications are the leading cause of death. The central pathological features of atherosclerosis are macrophage infiltration and foam cell formation, in which CD36 is crucial in activating macrophages and mediating the uptake of cholesterol. However, mechanisms regulating the activation of CD36 remain unclear. TRPM2 is an Ca2+permeable channel activated by oxidative stress, which occurs in the activation of macrophages.Hypothesis:We hypothesized that during atherosclerosis, TRPM2 is critical for the activation of CD36 in macrophages. Thus, Trpm2deletion inhibits macrophage activation and foam cell formation.Methods:ApoE-/-mice and ApoE-/-mice with Trpm2deletion were fed with high-fat food to induce atherosclerosis. Oil red O and immunofluorescence staining were performed to evaluate lipid deposition and macrophage load in aorta. Transwell assay was used to test macrophage infiltration and emigration. Oxidized LDL (oxLDL) or thrombospondin-1 (TSP1) was used to activate CD36. Western blot was used to examine the activation of CD36 signaling. ROS and Ca2+imaging were performed to examine the activation of macrophages by CD36.Results:Trpm2deletion: (1) reduced lesion ratio (0.13 ± 0.02 vs 0.36 ± 0.02) and macrophage load (20.93 ± 4.82 / mm2vs 60.20 ± 8.36 / mm2) in aorta; (2) inhibited oxLDL uptake (32.24 ± 7.65 % vs 100 %) by macrophages; (3) suppressed macrophage infiltration (15.83 ± 2.44 / mm2vs 46.83 ± 4.62 / mm2) and preserved macrophage emigration (15.5 ± 1.73 / mm2vs 5.0 ± 0.73 / mm2); (4) inhibited ROS production (5.32 ± 0.61 % vs 28.82 ± 1.48 %) and increase of intracellular Ca2+(2.92 ± 0.86 % vs 11.95 ± 1.60 %) in macrophages induced by oxLDL (n= 6 ~ 8 for all data). Also, oxLDL and TSP1 activated TRPM2 via CD36, and TRPM2 was required for the activation of CD36 signaling in macrophages by oxLDL or TSP1.Conclusions:In summary, TRPM2 and CD36 activated each other in macrophages, which promoted the development of atherosclerosis.