Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran; Student Research Committee, Department of Modern Science and Technology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
Peptides. 2019 Jan;111:142-151. doi: 10.1016/j.peptides.2018.04.002. Epub 2018 Apr 7.
Oxytocin (OT) has a postconditioning effect against the ischemia-reperfusion (I/R) injury. However, its precise cardioprotection mechanism at the early reperfusion phase remains under debate. Our previous study revealed that OT postconditioning (OTpost) is cardioprotective by activating the Reperfusion Injury Salvage Kinase (RISK) pathway. Therefore, the present study is aimed to determine the biological effects of OTpost via the OT receptor and the activation of the JAK/STAT3 signaling pathway, mitochondrial adenosine triphosphate-dependent potassium channel (mitoKATP), nitric oxide (NO) release, and its anti-apoptotic effects against I/R injury in an isolated rat heart model. Sixty-three rats were randomly allocated to one of nine groups. OT was perfused 40 min prior to the regional ischemia or 15 min at the early reperfusion phase. AG490 (a JAK/STAT3 inhibitor), 5HD (a mitoKATP blocker), atosiban (an OT receptor antagonist), L-NAME (a nonspecific nitric oxide synthase inhibitor) were applied either alone or in combination with OT during the pre-ischemia phase and/or in the early reperfusion phase. Myocardial infarct size, hemodynamic factor, ventricular arrhythmia, coronary flow, cardiac biochemical marker, and the apoptosis index were determined at the end of reperfusion. Oxytocin postconditioning reduced infarct size, lactate dehydrogenase activity, arrhythmia score, ventricular fibrillation, and apoptosis. Moreover, AG490, 5HD, atosiban, and L-NAME abrogated the cardioprotective effects of OT. Our results demonstrated that the cardioprotective effects of OT are mediated by NO release, and the activation of mitoKATP and the SAFE pathway through the JAK/STAT3 signaling cascade that finally lead to decrease in the apoptosis index during the early reperfusion phase.
催产素（OT）对缺血再灌注（I/R）损伤具有预处理作用。然而，其在再灌注早期的确切心脏保护机制仍存在争议。我们之前的研究表明，OT 后处理（OTpost）通过激活再灌注损伤挽救激酶（RISK）途径发挥心脏保护作用。因此，本研究旨在通过 OT 受体和 JAK/STAT3 信号通路的激活、三磷酸腺苷依赖性钾通道（mitoKATP）、一氧化氮（NO）释放及其对 I/R 损伤的抗凋亡作用，来确定 OTpost 的生物学效应，在大鼠离体心脏模型中。63 只大鼠随机分为 9 组中的一组。OT 在局部缺血前 40 分钟或再灌注早期 15 分钟灌注。AG490（JAK/STAT3 抑制剂）、5HD（mitoKATP 阻断剂）、阿托西班（OT 受体拮抗剂）、L-NAME（非特异性一氧化氮合酶抑制剂）在缺血前阶段单独或联合 OT 应用，或在再灌注早期阶段。在再灌注结束时测定心肌梗死面积、血流动力学因子、室性心律失常、冠脉流量、心脏生化标志物和细胞凋亡指数。OT 后处理减少了梗死面积、乳酸脱氢酶活性、心律失常评分、心室颤动和细胞凋亡。此外，AG490、5HD、阿托西班和 L-NAME 消除了 OT 的心脏保护作用。我们的结果表明，OT 的心脏保护作用是通过 NO 释放介导的，并且通过 JAK/STAT3 信号级联激活 mitoKATP 和 SAFE 途径，最终导致再灌注早期细胞凋亡指数降低。
