β-羟丁酸激活claudin-5表达干预糖尿病心脏微血管病变的机制

紧密连接蛋白claudin-5表达不足，致内皮高通透性，是糖尿病心脏微血管病变的起始环节和病理基础。我们预实验发现，高糖刺激β-catenin与p300及基因启动子结合障碍，是claudin-5表达不足的核心。β-羟丁酸是新发现的基因调控小分子，具有良好心血管保护功能。那么在糖尿病微血管病变中，β-羟丁酸是否通过调控β-catenin/p300，激活claudin-5表达而起到干预作用呢？本研究采用心脏微血管内皮细胞进行体内、外实验，首先明确β-羟丁酸拮抗高糖所致claudin-5表达不足的基础上，从β-catenin和p300的结合活性；β-catenin/p300与claudin-5基因启动子的结合活性；p300的酶活性方面，深入研究β-羟丁酸调控β-catenin/p300，激活claudin-5表达的分子机制和作用靶点，在病变的起始环节，为糖尿病心脏微血管病变的有效防治提供新思路。

The insufficient expression of tight junction protein claudin-5 can lead to endothelial hyperpermeability, which is the initiating process and pathological basis of diabetic micro-cardiovascular disease. Our pre-experiment shows that the intrinsic mechanism of the down-regulation of claudin-5 may be attributed to the high glucose-stimulated binding dysfunction of β-catenin to p300 and the gene promoter. β-hydroxybutyrate is a new-found small molecule that regulates gene expression, and it has satisfactory protective effects on cardiovascular system. Whether β-hydroxybutyrate activates claudin-5 by regulating β-catenin/p300 to have intervention effects in diabetic micro-cardiovascular disease? In this study, cardiac microvascular endothelial cells are adopted to perform experiments in vivo and in vitro. On the basis that β-hydroxybutyrate antagonizes the high glucose-induced insufficiency of claudin-5 expression, in the aspects of the binding activity of β-catenin to p300, the binding activity of β-catenin/p300 to claudin-5 gene promoter, and the enzyme activity of p300, the molecular mechanism and effect targets of β-hydroxybutyrate in regulating β-catenin/p300 to activate claudin-5 are further investigated to provide new thinking of the effective prevention and treatment of diabetic micro-cardiovascular disease in the initiating process.