辣椒素受体介导吴茱萸次碱抑制动脉粥样硬化血管病变及缝隙连接重构作用

The pathogenesis of atherosclerosis is complex，which involved the whole vascular pathalogical changes. The dysfuction of vascular endothlium is supposed to be the onset of atherosclerosis, so protection of vascular endothlium and then inhibition of adhesion and migration of monocyte,and proliferation of smooth muscle cell, is important for anti-atherosclerosis. Gap junction(GJ) is special membrane channels mediating direct communication between adjacent cells. Gap junction arise from the docking of two hemichannels, formed by six connexins(Cx). In recent years, a large number of studies have shown that, the GJ remodeling which including the change of the site, type and quantity of Cx expression, is closely related to the development of the vascular lesions in atherosclerosis. Rutaecarpine (Rut), the active ingredients of traditional Chinese medicine Evodia, has extensive cardiovascular effects,such as vasodilatory, antihypertensive and myocardial protective effects,which has been proved to be associated with the activation of the transient receptor potential vanilloid subtype 1 (TRPV1). Our preliminary experiment showed that, Rut could inhibit endothelial damage induced by Ox-LDL, and improve endothelial GJ intercellular communition, which is related to the activation of TRPV1. So the aim of the present project was to explore the anti-atherosclerosis effect of Rut，observe the vascular protection of Rut systematically in atherosclerosis model of in vivo and in vitro , and study whether the mechanism is related to Cx37，40，43，which were the hotspot in atherosclerosis. Furthermore,we will explore the signaling pathway of TRPV1 regulating GJ remodeling. This study maybe contribute to promote the modernization of traditional Chinese medicine , and provide a new target to find drugs for atherosclerosis.

动脉粥样硬化（AS）涉及全血管生物学病理改变，其中血管内皮损伤是AS发生的始动环节，保护血管内皮，抑制后续的单核细胞黏附和平滑肌增殖迁移是抗AS治疗的重要策略。缝隙连接(GJ)为沟通相邻细胞的细胞间通道，由连接蛋白（Cx)组成，是细胞间进行物质和能量交流的直接通讯方式。近年来的大量研究表明，AS时Cx表达的部位、类型及数量的改变导致的GJ重构与AS血管病变的发生发展密切相关。吴茱萸次碱(Rut)为传统中药吴茱萸的有效成分，具有广泛的心血管效应，其舒血管、降压及心肌保护作用均与激活辣椒素受体（TRPV1）有关。本项目旨在进一步发掘Rut的抗AS作用，从细胞和整体水平系统研究Rut对AS血管病变的作用，并观察Rut对与AS相关的热点分子Cx37、40和43表达及GJ细胞间通讯的影响，在此基础上进一步探索TRPV1调节GJ的信号通路。旨在促进中药现代化, 为开发新作用靶点的抗AS药物提供靶点。

动脉粥样硬化（AS）涉及全血管生物学病理改变，保护血管内皮，抑制后续的单核细胞黏附和平滑肌增殖迁移是抗AS治疗的重要策略。缝隙连接(GJ)为沟通相邻细胞胞质的细胞间通道，由连接蛋白（Cx)组成，是细胞间进行物质和能量交流的直接通讯方式。近年来的大量研究表明，AS时Cx表达的部位、类型及数量的改变导致的GJ重构与AS血管病变的发生发展密切相关。吴茱萸次碱(Rut)为传统中药吴茱萸的有效成分，具有广泛的心血管效应，其舒血管、降压及心肌保护作用均与激活辣椒素受体（TRPV1）有关。本项目在致AS因素Ox-LDL诱导的细胞模型观察Rut对与AS相关的热点分子Cx37、40和43表达的影响。在三种不同细胞模型（血管内皮细胞、单核细胞、血管平滑肌细胞）的研究均发现Rut可逆转Ox-LDL诱导的Cxs表达谱改变，恢复有抗AS作用的 Cx37、40的表达，而抑制有促AS效应的Cx43的表达，从而改善内皮功能，抑制单核-内皮细胞黏附，抑制VSMC的增殖、迁移和表型转换，并确定RUT 调节Cxs的机制与激活TRPV1/[Ca2+]i信号通路有关。该发现有助于进一步发掘Rut的抗AS作用，为开发新作用靶点的抗AS药物提供思路。