TRPM2型
CD36
泡沫电池
炎症
癌症研究
巨噬细胞
氧化应激
清道夫受体
化学
受体
免疫学
细胞生物学
瞬时受体电位通道
生物
脂蛋白
胆固醇
生物化学
体外
作者
Pengyu Zong,Jianlin Feng,Zhichao Yue,Albert S. Yu,Jean Vacher,Evan R. Jellison,Barbara A. Miller,Yasuo Mori,Lixia Yue
标识
DOI:10.1038/s44161-022-00027-7
摘要
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. Zong and colleagues reveal a critical role for the ion channel TRPM2 in macrophages through mediating reactive oxygen species production, inflammasome activation, oxidized LDL uptake and subsequently inflammatory responses, which they show is mediated by CD36 activity, thereby establishing a mutually regulating and positive feedback mechanism between CD36 and TRPM2 in atherogenesis.
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