Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Eur J Pharmacol. 2020 May 5;874:172987. doi: 10.1016/j.ejphar.2020.172987. Epub 2020 Feb 4.
Mitochondrial dynamics, determining mitochondrial morphology, quality and abundance, have recently been implicated in myocardial ischemia and reperfusion (MI/R) injury. The roles of κ-opioid receptor activation in cardioprotection have been confirmed in our previous studies, while the underlying mechanism associated with mitochondrial dynamics remains unclear. This study aims to investigate the effect of κ-opioid receptor activation on the pathogenesis of MI/R and its underlying mechanisms. MI/R mouse model and hypoxia-reoxygenation cardiomyocyte model were established in this study. Mitochondrial dynamics were analyzed with transmission electron microscopy in vivo and confocal microscopy in vitro. STAT3 phosphorylation and OPA1 expression were detected by Western blotting. We show here that κ-opioid receptor activation with its selective receptor agonist U50,488H promoted mitochondrial fusion and enhanced myocardial resistance to MI/R injury, while these protective effects were blockaded by nor-BNI, a selective κ-opioid receptor antagonist. In addition, κ-opioid receptor activation increased STAT3 phosphorylation and OPA1 expression, which were blockaded by nor-BNI. Furthermore, inhibition of STAT3 phosphorylation by stattic, a specific STAT3 inhibitor, repressed the effects of κ-opioid receptor activation on promoting OPA1 expression and mitochondrial fusion, as well as inhibiting cell apoptosis and oxidative stress both in vivo and in vitro during MI/R injury. Overall, our data for the first time provide evidence that κ-opioid receptor activation promotes mitochondrial fusion and enhances myocardial resistance to MI/R injury via STAT3-OPA1 pathway. Targeting the pathway regulated by κ-opioid receptor activation may be a potential therapeutic strategy for MI/R injury.
线粒体动力学决定了线粒体的形态、质量和丰度，最近与心肌缺血再灌注（MI/R）损伤有关。在我们之前的研究中已经证实了 κ 阿片受体激活在心脏保护中的作用，而与线粒体动力学相关的潜在机制仍不清楚。本研究旨在探讨 κ 阿片受体激活对 MI/R 发病机制的影响及其潜在机制。本研究建立了 MI/R 小鼠模型和缺氧复氧心肌细胞模型。通过体内透射电子显微镜和体外共聚焦显微镜分析线粒体动力学。通过 Western blot 检测 STAT3 磷酸化和 OPA1 表达。我们在这里表明，κ 阿片受体激活及其选择性受体激动剂 U50,488H 促进线粒体融合，增强心肌对 MI/R 损伤的抵抗力，而这些保护作用被选择性 κ 阿片受体拮抗剂 nor-BNI 阻断。此外，κ 阿片受体激活增加了 STAT3 磷酸化和 OPA1 表达，nor-BNI 阻断了这一作用。此外，特异性 STAT3 抑制剂 stattic 抑制 STAT3 磷酸化，抑制了 κ 阿片受体激活对促进 OPA1 表达和线粒体融合的作用，以及抑制 MI/R 损伤期间体内和体外的细胞凋亡和氧化应激。总的来说，我们的数据首次提供了证据，表明 κ 阿片受体激活通过 STAT3-OPA1 途径促进线粒体融合，增强心肌对 MI/R 损伤的抵抗力。靶向由 κ 阿片受体激活调节的途径可能是 MI/R 损伤的一种潜在治疗策略。
