NADPH氧化酶在钙化性主动脉瓣膜病中的作用研究

项目名称： NADPH氧化酶在钙化性主动脉瓣膜病中的作用研究

项目编号： No.81470506

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张敏

作者单位： 新乡医学院

项目金额： 73万元

中文摘要： 钙化性主动脉瓣膜病(CAVD)是老年社会所面临的严重临床问题，其主要表型特点是主动脉瓣膜间质细胞(AVIC)向成骨样细胞转化。活性氧(ROS)在CAVD中显著升高，但其来源及对细胞钙化的作用和机制仍不清楚。NADPH氧化酶(Nox)是重要ROS 来源，其在心血管疾病中作用是细胞特异性的。心脏主要表达Nox2和Nox4，研究显示在病理性心肌重构的过程中Nox2是有害的，但Nox4则起保护作用，Nox的这种特殊性为探讨瓣膜钙化的发病机制及其防治提供了新的靶向。本课题将从细胞﹑组织﹑动物和患者标本等多层次研究Nox在CAVD中的作用: 1.检测Nox不同亚型在正常瓣膜上的组织细胞特异性表达及在CAVD病变发展中的变化；2.明确Nox2/4对培养的AVIC钙化的影响；3.探讨内皮细胞和AVIC的相互作用及Nox2/4的旁分泌效应；4.可能的机制研究；5.观察 Nox抑制剂对兔CAVD的保护作用。

中文关键词： 主动脉瓣；瓣膜钙化；活性氧；NADPH氧化酶；瓣膜间质细胞

英文摘要： Calcific aortic valve disease (CAVD), a major clinical problem facing aging societies, is an actively regulated calcification process characterized by differentiation of aortic valvular interstitial cells (AVIC) toward an osteogenic-like phenotype. Emerging evidence indicates that reactive oxygen species (ROS) levels increase in aortic valve (AV) stenosis, however the sources of ROS and their roles in the pathogenesis of CAVD are elusive. NADPH oxidases (Nox) are important cardiac ROS-generating enzymes but the contributions of Nox in the (patho)physiological process of cardiovascular diseases are tissue-specific and isoform-dependent. The most abundant isoforms in the heart are Nox2 and Nox4. We and others demonstrated that Nox2 is detrimental but Nox4 beneficial in the process of adverse cardiac remodeling, the findings raising the question whether the distinctive involvement of Nox isoforms may provide potential targets for therapeutic manipulation in the development of CAVD. This project will investigate: (a) the spatial heterogeneity of Nox expressions in normal aortic valves, and their changing profiles with the development of CAVD in rabbits and patients; (b) the roles of Nox2/4 for the osteoblastic differentiation on cultured AVIC transduced with either adenoviral vectors overexpressing Nox2/4 or the short-hair pin sequences targeted against Nox2/4; (c) the interaction between endothelial cells and AVIC, and the paracrine effects of Nox2/4 on AVIC calcification; (d) mechanisms involved in such modulation; e) the protective effect of Nox inhibitor against CAVD in rabbit.

英文关键词： aortic valve;valve calcification;reactive oxygen species;NADPH oxidases;valvular interstitial cells