β-羟丁酸抗硝基化干预糖尿病心脏微血管病变的机制

项目名称： β-羟丁酸抗硝基化干预糖尿病心脏微血管病变的机制

项目编号： No.81470595

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： 齐锦生

作者单位： 河北医科大学

项目金额： 73万元

中文摘要： 血管基底膜增生是糖尿病心脏微血管病变的典型特征，病理基础为IV型胶原积聚。氧化应激导致的持续硝基化是核心病机，这也被我们前期研究所证实。内源性小分子β-羟丁酸具有良好的抗氧化、抗硝基化作用，主要在心血管系统起效。β-羟丁酸不同于传统抗氧化剂的独特性是调控基因表达。有报道，β-羟丁酸可逆转纤维化，但机制未明。本项目拟采用起主要病理作用的心脏微血管内皮细胞进行体内、外实验，首先在明确硝基化导致IV型胶原积聚的基础上，探寻β-羟丁酸调控IV型胶原来源和去路平衡的作用靶点，在基因调控水平，从Smad3与IV型胶原，和NF-κB与MMP-9基因启动子的结合活性；Smad3与共因子p300或HDAC3，和NF-κB与共因子p300或HDAC3的结合活性；p300、HDAC3和MMP-9酶活性方面，系统研究β-羟丁酸抗硝基化调控IV型胶原代谢平衡的作用靶点和机制，为糖尿病心脏微血管病变的防治提供新思路。

中文关键词： 血管内皮细胞；氧化应激；β-羟丁酸；硝基化；糖尿病心脏微血管病变

英文摘要： The typical feature of diabetic micro-cardiovascular disease is proliferation of vascular basement membrane, the pathological base of which is accumulation of collagen IV. The persistent nitration caused by oxidative stress is its core pathogenesis, which has also been proved by our previous study. The endogenous small molecule β-hydroxybutyrate has good effects of anti-oxidation and anti-nitration, to act mainly in cardiovascular system. The distinctness of β-hydroxybutyrate from conventional antioxidants is regulating gene expression. It is reported that β-hydroxybutyrate can reverse fibrosis, but the mechanism is not clarified. In this study, cardiac microvascular endothelial cells that play a major pathological role are adopted to perform experiments in vivo and in vitro. On the basis that nitration leads to accumulation of collagen IV, the effect target of β-hydroxybutyrate in regulating the generation and degradation balance of collagen IV is investigated. In the aspects of the binding activity of Smad3 to collagen IV gene promoter and NF-κB to MMP-9 gene promoter, the binding activity of Smad3 to the cofactor p300 or HDAC3 and NF-κB to the cofactor p300 or HDAC3, and the enzyme activity of p300, HDAC3 and MMP-9, the effect target and mechanism of β-hydroxybutyrate in regulating collagen IV metabolism balance by antagonizing nitration is systematically studied in the gene regulation level, to provide new thinking of the prevention and treatment of diabetic micro-cardiovascular disease.

英文关键词： vascular endothelial cells;oxidative stress;β-hydroxybutyrate;nitration;diabetic micro-cardiovascular disease