Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia.
Department of Physiology, College of Medicine, Umm Al-Qura University, Mekkah, Saudi Arabia.
Cardiovasc Toxicol. 2020 Aug;20(4):401-418. doi: 10.1007/s12012-020-09567-5.
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/2×/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-α and IL-6, as well as, the activation of NF-κB p65. In addition, exendin-4 inhibited the interaction of PARP1 with p300, TGF-β1, Smad3, and NF-κB 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.
Sirt1 是聚（ADP-核糖）聚合酶 1（PARP1）和 NF-κB 的有效抑制剂。本研究探讨了 exendin-4 在大鼠实验性心肌梗死（MI）后对心脏功能和重构的保护作用，并探讨了这种保护是否涉及 SIRT1/PARP1 轴。大鼠分为五组（每组 n = 10）：假手术组、假手术+exendin-4（25 nmol/kg/天腹腔注射）组、MI 组（通过 LAD 闭塞诱导）、MI+exendin-4 组和假手术+exendin-4+EX527（5 mg/2×/周）组（SIRT1 抑制剂）。所有治疗均在 MI 诱导后 6 周进行。在假手术和 MI 诱导的大鼠中，exendin-4 显著上调 Bcl-2 水平，增强 SIRT1 的活性、mRNA 和水平，抑制 PARP1 的活性、mRNA 和水平，并减少 ROS 生成和 PARP1 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、减少胶原沉积以及减少 TNF-α 和 IL-6 的 mRNA 和总水平以及 NF-κB p65 的激活有关。此外，exendin-4 抑制了 PARP1 与 p300、TGF-β1、Smad3 和 NF-κB p65 的相互作用，并显著降低了胶原 I/III 的 mRNA 和蛋白水平以及 MMP2/9 的蛋白水平。总之，exendin-4 是一种有效的心脏保护剂，可通过激活 SIRT1 诱导的 PARP1 抑制来防止 MI 后炎症和心脏重构。
