Exendin-4 Ameliorates Cardiac Remodeling in Experimentally Induced Myocardial Infarction in Rats by Inhibiting PARP1/NF-κB Axis in A SIRT1-Dependent Mechanism
Exendin-4 Ameliorates Cardiac Remodeling in Experimentally Induced Myocardial Infarction in Rats by Inhibiting PARP1/NF-κB Axis in A SIRT1-Dependent Mechanism
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DOI：
10.1007/s12012-020-09567-5
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发表时间：
2020-03-19
影响因子：
3.2
通讯作者：
Al-Shudiefat, Abd Al-Rahman Salem
中科院分区：
文献类型：
--
作者：
Eid, Refaat A.;Alharbi, Samah A.;Al-Shudiefat, Abd Al-Rahman Salem
Sirt 1是聚（ADP-核糖）聚合酶1（PARP 1）和NF-κ B的有效抑制剂。本研究探讨exendin-4对实验性心肌梗死（MI）大鼠心功能和重构的保护作用，并探讨这种保护作用是否涉及SIRT 1/PARP 1轴。将大鼠分为五组（n = 10/每组）：假手术组、假手术+毒蜥外泌肽-4（25 nmol/kg/天，腹膜内）、MI（由LAD闭塞诱导）、MI +毒蜥外泌肽-4和假手术+毒蜥外泌肽-4 + EX 527（5 mg/2x/周）（SIRT 1抑制剂）。所有治疗均在诱导MI后给予6周。在假手术和MI诱导的大鼠中，exendin-4显著上调Bcl-2水平，增强SIRT 1的活性、mRNA和水平，抑制PARP 1的活性、mRNA和水平，并减少ROS生成和PARP 1乙酰化。在MI治疗的大鼠中，这些作用与改善心脏结构和LV功能、减少胶原沉积、降低TNF-α和IL-6的mRNA和总水平以及NF-κ B p65的活化相关。此外，exendin-4抑制PARP 1与p300、TGF-β 1、Smad 3和NF-κ B p65的相互作用，并显著降低胶原I/III的mRNA和蛋白水平以及MMP 2/9的蛋白水平。总之，exendin-4是一种有效的心脏保护剂，通过激活SIRT 1诱导的PARP 1抑制来预防MI后炎症和心脏重塑。
Sirt1 is a potent inhibitor of both poly(ADP-ribose) polymerases1 (PARP1) and NF-kB. This study investigated the cardioprotective effect of exendin-4 on cardiac function and remodeling in rats after an expreimentally-induced myocardial infarction (MI) and explored if this protection involves SIRT1/PARP1 axis. Rats were divided into five groups (n = 10/each): sham, sham + exendin-4 (25 nmol/kg/day i.p.), MI (induced by LAD occlusion), MI + exendin-4, and sham + exendin-4 + EX527 (5 mg/2x/week) (a SIRT1 inhibitor). All treatments were given for 6 weeks post the induction of MI. In sham-operated and MI-induced rats, exendin-4 significantly upregulated Bcl-2 levels, enhanced activity, mRNA, and levels of SIRT1, inhibited activity, mRNA, and levels of PARP1, and reduced ROS generation and PARP1 acetylation. In MI-treated rats, these effects were associated with improved cardiac architectures and LV function, reduced collagen deposition, and reduced mRNA and total levels of TNF-alpha and IL-6, as well as, the activation of NF-kappa B p65. In addition, exendin-4 inhibited the interaction of PARP1 with p300, TGF-beta 1, Smad3, and NF-kappa B p65 and signficantly reduced mRNA and protein levels of collagen I/III and protein levels of MMP2/9. In conclusion, exendin-4 is a potent cardioprotective agent that prevents post-MI inflammation and cardiac remodeling by activating SIRT1-induced inhibition of PARP1.