TRPM2 deficiency in mice protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages.
TRPM2 deficiency in mice protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages.
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DOI：
10.1038/s44161-022-00027-7
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发表时间：
2022-04
期刊：
影响因子：
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通讯作者：
Yue, Lixia
中科院分区：
文献类型：
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作者：
Zong, Pengyu;Feng, Jianlin;Yue, Zhichao;Yu, Albert S;Vacher, Jean;Jellison, Evan R;Miller, Barbara;Mori, Yasuo;Yue, Lixia
动脉粥样硬化是导致缺血性心脏病和中风的主要原因，也是世界范围内导致死亡的主要原因。动脉粥样硬化的主要病理特征是巨噬细胞的浸润和泡沫细胞的形成。然而，监管这两个过程的详细机制仍不清楚。在这里，我们证明了氧化应激激活的钙离子可穿透的瞬时受体潜能Melastatin 2(TRPM2)在动脉粥样硬化形成中起着关键作用。全局和巨噬细胞特异性的TRPM2缺失均可保护APOE−/−小鼠免受动脉粥样硬化的影响。TRPM2缺乏降低了巨噬细胞对氧化低密度脂蛋白(OxLDL)的摄取，从而最大限度地减少了巨噬细胞的渗透、泡沫细胞的形成和炎症反应。OxLDL受体CD36的激活可诱导TRPM2活性，反之亦然。在培养的巨噬细胞中，TRPM2被CD36配体oxLDL和TSP1激活，删除TRPM2或抑制TRPM2活性可抑制oxLDL和TSP1诱导的CD36信号级联激活。我们的发现确立了TRPM2-CD36轴是动脉粥样硬化形成的分子机制，并提示TRPM2是治疗动脉粥样硬化的潜在靶点。
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 remain 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 deletion 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 CD36 ligands oxLDL and thrombospondin-1 (TSP1), and deleting Trpm2 or inhibiting TRPM2 activity suppresses the activation of 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.