Sirt1调控Nrf2信号通路对心肌缺血再灌注中氧化应激损伤的作用研究

心肌缺血再灌注（MI/R）损伤的发生发展与氧化应激密切相关。近期研究发现抑制Sirt1的表达会加重MI/R中心肌组织的氧化应激损伤，但其机制尚未完全阐明。Nrf2是重要的内源性抗氧化应激通路。文献报道及我们前期研究表明，激活Nrf2可显著增强心肌组织抗氧化应激能力进而减轻心肌损伤，且Sirt1可通过影响Nrf2的活化降低细胞内ROS的水平。据此，我们提出假说：Sirt1通过影响Nrf2的乙酰化，促进Nrf2核内定位进而增加其转录活性，增加下游抗氧化类蛋白表达，启动抗氧化应激机制，最终减少MI/R中心肌细胞凋亡。我们拟通过MI/R细胞和动物模型，运用分子生物学、生物化学等技术，研究Sirt1对Nrf2活化的调控作用和具体机制，并进一步研究其在缺血再灌注引起的氧化应激损伤中的作用。本课题将从Sirt1/Nrf2这个新视点研究增强机体内源性抗氧化应激系统的机制，为MI/R的治疗提供新的思路。

Oxidative stress is the putative common mechanism of myocardial ischemia/reperfusion injury (MI/R). Latest studies found that inhibition of Sirt1 could deteriorate the oxidative stress injury in heart tissue. Nrf2 is one of the most important endogenous antioxidant stress pathways. Previous reports and our preliminary data showed that activation of Nrf2 could decrease the intracellular ROS content and increase the resistance of cardiomyocytes to oxidative stress during MI/R injury. Importantly, Sirt1 could regulate the activation of Nrf2 to reduce the intracellular ROS content. However, mechanisms for such an action have yet to be investigated. Thus, we hypothesized that Sirt1 regulates the transcriptional activity and nucleocytoplasmic localization of Nrf2 by decreasing its acetylation, leading to the enhanced cell survival against MI/R injury. On the basis of the preliminary experiments, our project would establish animal and cell model to verify this scientific hypothesis. The validation of this hypothesis will suggest a new idea for researching the effective therapy of MI/R, which is of important theoretical significance and application value.