高同型半胱氨酸血症激活巨噬细胞TRPV1促易损斑块形成机制研究

巨噬细胞脂代谢紊乱和凋亡是促进易损斑块形成的主要因素。TRPV1作为非选择性阳离子通道，通过LXRα和内质网应激（ERS）调控细胞脂代谢和凋亡。本组前期研究显示：高同型半胱氨酸血症（HHcy）诱导小鼠主动脉斑块TRPV1表达和易损斑块形成，体外阻断TRPV1可缓解由HHcy诱导的巨噬细胞凋亡，提示TRPV1可能是HHcy促易损斑块形成的关键因子。故本项目提出：HHcy通过激活TRPV1介导的巨噬细胞泡沫化和凋亡促进易损斑块形成。本项目拟复制HHcy模型，分析TRPV1变化，在细胞中使其沉默和过表达，明确 HHcy调控TRPV1介导巨噬细胞泡沫化和凋亡作用，分析TRPV1调控LXRα和ERS促进易损斑块形成的分子调控机制，并探讨阻断TRPV1改善HHcy诱导易损斑块作用。本项目将阐明HHcy激活巨噬细胞TRPV1促进易损斑块形成的作用和机制，为逆转易损斑块形成提供干预靶点。

Lipid metabolism disorders and macrophage apoptosis are major causes of promoting the formation of vulnerable plaques. TRPV1 is a nonselective cation channel that plays an important role in regulating lipid metabolism via inhibition of LXR α and apoptosis via endoplasmic reticulum stress(ERS).Our previous study indicated that hyperhomocysteinemia (HHcy) induced the expression of TRPV1 in the mouse aorta, and promoted the formation of vulnerable atherosclerotic plaques in vivo. In addition, while knockdown of TRPV1 attenuated Hcy-induced macrophage apoptosis in vitro. We therefore hypothesized that " Activation TRPV1 by HHcy in macrophages promotes macrophage foam cell formation and macrophage apoptosis, results in the formation of vulnerable atherosclerotic plaques". In the present project, the macrophage cell line and ApoE-/- mice fed on high methionine diet will be used to establish an HHcy-induced atherosclerosis (AS) model. We will detect TRPV1 and verify the crucial role of TRPV1 mediated lipid metabolism disorder and apoptosis in vulnerable plaque by knockdown and overexpression TRPV1, in an attempt to elucidate the mechanism underlying TRPV1 inhibition of LXRα and activation ERS in HHcy-induced formation of vulnerable atherosclerotic plaques, and explore the protective effect of TRPV1 inhibition on HHcy-induced formation of vulnerable atherosclerotic plaques in mice. We hope that the results obtained from the study could help clarify TRPV1 as an Hcy sensor in activating macrophage-derived foam cell formation and macrophage apoptosis to promote the formation of vulnerable atherosclerotic plaques and further understand the physiological function of TRPV1, thus providing useful references for using TRPV1 as a potential drug target for the treatment of HHcy-indcued AS.