VSMC源性血管紧张素转化酶通过C-结构域促动脉粥样硬化的作用及机制研究

Atherosclerosis is one of the world's leading killers. We have previously demonstrated that Renin-angiotensin-system (RAS) plays an important role in the development of atherosclerosis, and angiotensin (Ang)II could be up-regulated in hyperlipidemia induced atherosclerosis. In addition, AngII infusion into LDLr-/- mice promoted high fat diet induced atherosclerosis. Angiotensin-converting enzyme (ACE) is the main enzyme to convert angiotensin (Ang) I into AngII. We have reported that ACE inhibitors significantly prevented high-fat diet induced atherosclerosis in LDLr-/- mice through an AngII-dependent mechanism. However, the mechanisms underlying the contribution of ACE in atherosclerosis has not been addressed. Firstly, ACE is a type I transmembrane protein containing two extracellular catalytic domains termed amino (N) and carboxyl (C). Genetic mutation has demonstrated C domain is the preferred site for AngI conversion into AngII while N domain is the preferred site for breaking down bradyknin. Currently used ACE inhibitors can inhibit both active sites efficiently and easily lead to side effects such as coughing. Therefore whether ACE contributes to atherosclerosis through its C-domain need to be defined. Secondly, in recent years, there is hot debate on whether atherogenic angiotensin peptides are produced systemically or locally. The role of cell-specific ACE in atherosclerosis is unclear. Smooth muscle cells are the most abundant cell type in atherosclerotic lesions. In my preliminary studies, ACE protein was present in atherosclerotic lesions, and primarily co-localized with SMCs in the lesions. We have successfully developed hypomorphic ACE mice, in which only the function of C-domain is significantly inhibited whiling keeping the function of N-domain. We have also developed SMCs-specific ACE (C-domain) knockout mice, On the basis of our preliminary findings, I am proposing to test the hypothesis that VSMCS derived ACE contributes to hypercholesteromia-induced atherosclerosis through the function of its C-domain. The inflammation regulation related mechanism underlying the role of VSMCS specific ACE will also be defined.

动脉粥样硬化性心血管病严重危害人类健康，是人类的头号杀手。肾素-血管紧张素系统(Renin Angiotensin System, RAS)在动脉粥样硬化发病中起重要作用，阐明RAS相关动脉粥样硬化的发病机制，进行有效地动脉粥样硬化防治已引起广泛关注。我们前期发现RAS系统末端活性效应物血管紧张素II (AngII) 在动脉粥样硬化中表达上调并可促进动脉粥样硬化进展。ACE抑制剂可通过AngII依赖性途径阻止高脂喂养诱导的动脉粥样硬化，提示ACE在该病理中扮演重要角色。然而，ACE在动脉粥样硬化中作用机制尚未阐明。本项目拟在前期工作基础上，研究VSMCs源性ACE通过C结构域对动脉粥样硬化的作用及调控机制，揭示VSMC靶向ACE (C结构域)基因敲除对动脉粥样硬化的保护作用及细胞炎症反应相关的非血压依赖性调控机制，为动脉粥样硬化的干预提供新靶点。