Abstract 17182: The Role of ROS Sensitive TRPM2 Mediated Inflammation in Atherosclerosis

Introduction: A variety of cardiovascular diseases stem from the manifestations of subclinical atherosclerosis, whose growth is fueled by inflammatory cytokines produced by macrophage-derived foam cells. A better understanding of the mechanisms underlying atherosclerosis will provide novel insights on potential therapeutic approaches for atherosclerosis associated cardiovascular diseases. The Ca 2+ -permeable TRPM2 which is activated by various reactive oxygen species (ROS) under stress conditions, is highly expressed in monocytes and macrophages. Our objective is to understand how TRPM2 in monocytes/macrophages mediates inflammation in atherosclerosis. Our hypothesis is that monocyte/macrophage TRPM2 is activated in the oxidative environment of atherosclerosis, and blocking TRPM2 will attenuates initiation and progression of atherosclerosis, thereby mitigating atherosclerotic cardiovascular disease. Methods: ApoE-deficient mice with Trpm2 deletion (APOE-TRPM2 double knockout: DKO) mice were fed with a high fat diet (HFD) to generate atherosclerosis. TRPM2 activity was measured by patch-clamp electrophysiology using peritoneal macrophages (PMs) obtained from DKO mice fed with HFD. Peripheral blood cells were collected from the tail vein and analyzed by flow cytometry. Results: We found that atherosclerosis plaque area was significantly reduced in HFD-fed DKO mice in comparison with the HFD-fed ApoE-KO mice (p<0.001). The TRPM2 channel activity and TRPM2 mediated Ca 2+ entry in macrophages were markedly higher in ApoE-KO mice fed with HFD than the ApoE-KO mice fed with normal chow, suggesting that TRPM2 may play a role in the atherosclerosis (p<0.05). Moreover, TRPM2 deletion drastically reduced IL-β production in PMs induced by LPS. Furthermore, we found that Trpm2-KO led to a 17% reduction of the inflammatory circulating myeloid cells in the ApoE-TRPM2 DKO mice compared to ApoE-KO mice fed with HFD (p<0.005). Conclusions: Our results indicate that deletion of TRPM2 reduces atherosclerotic plaques. Both inflammatory cytokine IL-1β production and inflammatory macrophages are reduced by TRPM2 deletion, indicating that the mechanisms by which TRPM2 inhibition deletion reduces atherosclerosis is through inhibiting inflammation during the atherosclerosis. As oxidative stress is a hallmark of atherosclerotic plaques, targeting monocyte/macrophage TRPM2 may serve as a novel approach to halt initiation and progression of atherosclerosis, as well as atherosclerotic cardiovascular diseases.