Claudin-1及其甲基化在沉默信息调控因子1保护缺血再灌注心肌机制中的作用

我们发现：沉默信息调控因子1（SIRT1）活化有显著抗心肌缺血再灌注损伤（IRI）作用，也是姜黄素心肌保护作用的重要途径，但下游分子不明。有报道，细胞间紧密连接蛋白Claudin-1基因有甲基化位点，特异性抑制此蛋白可减轻心肌IRI，且Claudin-1与SIRT1表达水平负相关。由此我们认为：缺血再灌注时，SIRT1的下调致claudin-1基因去甲基化和蛋白表达上调，是心肌IRI的重要机制。我们拟采用sirt1和claudin-1基因敲除(抑制)/过表达小鼠和细胞模型探讨：① Claudin-1及其甲基化在心肌IRI中的作用；② Claudin-1及其甲基化介导SIRT1抗心肌IRI机制；③ 姜黄素是否激活SIRT1，进而调节Claudin-1表达及其甲基化发挥心肌保护作用。这将有助于阐明IRI中Claudin-1与SIRT1的关系，为以姜黄素为基础的心肌保护药物临床应用奠定理论基础。

Our previous work indicated that the activation of silent information regulator 1 (SIRT1) had significant protective effect against myocardial ischemia-reperfusion injury (IRI), and was also played an important role in the mechanism of myocardial protection exerted by curcumin. But the downstream pathway of SIRT1 was not exactly investigated till now. It was reported that, the gene of an intercellular tight junction protein, Claudin-1, had methylational sites. Specifically inhibition of Claudin-1 could ameliorate myocardial IRI, and the expression of Claudin-1 was negatively related to SIRT1 activity. Therefore, we believe that during myocardial IRI, functionally inactivation of SIRT1 will induce a de-methylation process to Claudin-1 gene, and up-regulate the expression of Claudin-1, which is an important mechanism of myocardial IRI. We will use sirt1 and claudin-1 gene knock-out and over-expression mice and cell models to investigate: (1) the role of Claudin-1 and its methylation in myocardial IRI; (2) the role of SIRT1 in the modulation of Claudin-1 and its methylation against myocardial IRI; (3) whether curcumin’s protective effects against myocardial IRI is mediated by SIRT1 activation and further regulation of Claudin-1 level and its methylation. Answer these questions will be helpful to elucidate the relationship of Claudin-1 and SIRT1 in the set of myocardial IRI, and provide theoretical foundation for the clinical application of curcumin based myocardial protective drugs.