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Exendin-4 Protects Against Myocardial Ischemia-Reperfusion Injury by Upregulation of SIRT1 and SIRT3 and Activation of AMPK
Exendin-4 通过上调 SIRT1 和 SIRT3 及激活 AMPK 保护心肌缺血再灌注损伤
- 影响因子:2.09
- DOI:10.1007/s12265-020-09984-5
- 作者列表:"Eid, Refaat A.","Bin-Meferij, Mashael Mohammed","El-kott, Attalla Farag","Eleawa, Samy M","Zaki, Mohamed Samir Ahmed","Al-Shraim, Mubarak","El-Sayed, Fahmy","Eldeen, Muhammad Alaa","Alkhateeb, Mahmoud A.","Alharbi, Samah A.","Aldera, Hussain","Khalil, Mohammad A.
- 发表时间:2020-04-01
Abstract
This study evaluated if the cardioprotective effect of Exendin-4 against ischemia/reperfusion (I/R) injury in male rats involves modulation of AMPK and sirtuins. Adult male rats were divided into sham, sham + Exendin-4, I/R, I/R + Exendin-4, and I/R + Exendin-4 + EX-527, a sirt1 inhibitor. Exendin-4 reduced infarct size and preserved the function and structure of the left ventricles (LV) of I/R rats. It also inhibited oxidative stress and apoptosis and upregulated MnSOD and Bcl-2 in their infarcted myocardium. With no effect on SIRTs 2/6/7, Exendin-4 activated and upregulated mRNA and protein levels of SIRT1, increased levels of SIRT3 protein, activated AMPK, and reduced the acetylation of p53 and PGC-1α as well as the phosphorylation of FOXO-1. EX-527 completely abolished all beneficial effects of Exendin-4 in I/R-induced rats. In conclusion, Exendin-4 cardioprotective effect against I/R involves activation of SIRT1 and SIRT3. Graphical Abstract Exendin-4 could scavenge free radical directly, upregulate p53, and through upregulation of SIRT1 and stimulating SIRT1 nuclear accumulation. In addition, Exendin-4 also upregulates SIRT3 which plays an essential role in the upregulation of antioxidants, inhibition of reactive oxygen species (ROS) generation, and prevention of mitochondria damage. Accordingly, SIRT1 induces the deacetylation of PGC-1α and p53 and is able to bind p-FOXO-1. This results in inhibition of cardiomyocyte apoptosis through increasing Bcl-2 levels, activity, and levels of MnSOD; decreasing expression of Bax; decreasing cytochrome C release; and improving mitochondria biogenesis through upregulation of Mfn-2.
摘要
本研究评估了 Exendin-4 对雄性大鼠缺血/再灌注 (I/R) 损伤的心脏保护作用是否涉及 AMPK 和 sirtuins 的调节。成年雄性大鼠分为 sham 、 sham + Exendin-4 、 I/R + Exendin-4 和 sirt1 抑制剂 I/R + Exendin-4 + EX-527。Exendin-4 缩小了 I/R 大鼠的梗死面积,保留了左心室的功能和结构。它还抑制氧化应激和细胞凋亡,上调梗死心肌 MnSOD 和 Bcl-2。对 SIRTs 2/6/7 没有影响,Exendin-4 激活并上调 SIRT1 的 mRNA 和蛋白水平,增加 SIRT3 蛋白水平,激活 AMPK,并降低 p53 和 pgc-1 α 的乙酰化以及 FOXO-1 的磷酸化。EX-527 完全消除了 Exendin-4 在 I/R 诱导大鼠中的所有有益作用。总之,对 I/R Exendin-4 的心脏保护作用涉及 SIRT1 和 sirt3 的激活。Exendin-4 可以直接清除自由基,上调 p53,并通过上调 SIRT1 和刺激 SIRT1 核积累。此外,Exendin-4 还上调 SIRT3,SIRT3 在抗氧化剂的上调,抑制活性氧 (ROS) 生成和防止线粒体损伤中起重要作用。因此,SIRT1 诱导 pgc-1 α 和 p53 的去乙酰化,并能够结合 p-FOXO-1。这导致通过增加 Bcl-2 水平、活性和 MnSOD 水平来抑制心肌细胞凋亡; 降低 Bax 的表达; 减少细胞色素 C 的释放; 并通过上调 Mfn-2 来改善线粒体的生物合成。
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