Nrf2-sestrin2信号通路在木犀草素抑制糖尿病心脏缺血再灌注损伤中的作用及机制研究

Morbidity of diabetes is still increasing in recent years. Diabetic hearts are more susceptible to ischemia-reperfusion (IR) injury with a poorer prognosis than non-diabetic ones. It is known that nuclear factor-E2-related factor 2 (Nrf2) is a main regulator of endogenous antioxidants in the body. Our recent studies showed that luteolin, a flavone rich in vegetables, fruits, and nuts, protects the diabetic heart against IR injury by upregulating the myocardial eNOS pathway, and downstream effects include the enhancement of MnSOD and inhibition of the mitochondrial permeability transition pore (mPTP). We found that luteolin prevented the IR injury in diabetic hearts not only by activating eNOS, but also by increasing the Nrf2 function, sestrin2 and phosphorylated Akt expressions along with significant decreasing of oxidative stress, suggesting the upregulation of eNOS/Akt-Nrf2-sestrin2 might be a new key endogenous antioxidant pathway to prevent diabetic myocardial IR injury. On the basis of our previous study, we will use pharmacological blockers and siRNA to investigate the cardiac protection by luteolin against IR injury in the diabetic heart, and to clarify whether luteolin prevents the diabetic myocardial IR injury by activating Nrf2-sestrin2 pathway via upregulation of eNOS/Akt. This project will provide a new potential clinical therapeutic target and help to develop new drugs for diabetic cardiovascular complications in future.

内源性抗氧化应激机制减弱是糖尿病心脏容易发生缺血再灌注（IR）损伤且预后更差的重要原因。Nrf2在抵抗肥胖、糖尿病等代谢综合征导致的氧化应激损伤中发挥枢纽作用。我们证实木犀草素不仅通过上调心肌eNOS及MnSOD改善氧化应激，从而抑制线粒体渗透性转换孔（mPTP）开放减轻糖尿病心脏IR损伤；还上调了Akt、Nrf2功能和sestrin2表达。由此推测，木犀草素激活糖尿病心脏eNOS/Akt-Nrf2-sestrin2内源性抗氧化应激通路，可能是防治糖尿病心脏IR损伤的一种新的重要机制。本项目基于前期研究，拟在糖尿病心脏IR损伤动物和细胞模型采用药理学抑制剂及siRNA等工具药，解析木犀草素是否通过上调eNOS与Akt途径激活Nrf2-sestrin2回路对抗氧化应激诱导的mPTP开放及糖尿病心脏IR损伤，为积极干预糖尿病心血管并发症及新药开发提供有效的潜在治疗靶点和理论依据。

内源性抗氧化应激机制减弱是糖尿病心脏容易发生缺血再灌注（IR）损伤且预后更差的重要原因。Nrf2在抵抗肥胖、糖尿病等代谢综合征导致的氧化应激损伤中发挥枢纽作用。我们证实木犀草素不仅通过上调心肌eNOS促进Keap1 s-亚硝基化，从而促进Nrf2核转位上调内源性抗氧化酶表达，最终抑制线粒体渗透性转换孔（mPTP）开放减轻糖尿病心脏IR损伤，还通过上调Akt促进了sestrin2表达，后者也介导了木犀草素对糖尿病IR心脏的保护作用。我们还发现Nrf2与sestrin2之间存在这正反馈相互作用，共同参与木犀草素抑制糖尿病心脏IR损伤。由此推测，木犀草素通过上调eNOS与Akt途径激活Nrf2-sestrin2抗氧化应激正反馈回路对抗mPTP开放，是防治糖尿病心脏IR损伤的一种新的重要机制。本项目研究结果为积极干预糖尿病心血管并发症及新药开发提供有效的潜在治疗靶点和理论依据。