Abstract

This study investigated the protective effect of dapagliflozin on H9c2 cardiomyocyte function under high glucose and hypoxia/reoxygenation (HG-H/R) conditions and identified the underlying molecular mechanisms. Dapagliflozin reduced the level of lactate dehydrogenase and reactive oxygen species in cardiomyocytes under HG-H/R conditions and was accompanied by a decrease in caspase-3/9 activity. In addition, Dapagliflozin significantly reduced mitochondrial permeability transition pore opening and increased ATP content, accompanied by upregulation of OPA1 with autophagy-related protein molecules and activation of the AMPK/mTOR signalling pathway in HG-H/R treated cardiomyocytes. OPA1 knockdown or compound C treatment attenuated the protective effects of dapagliflozin on the cardiomyocytes under HG-H/R conditions. Downregulation of OPA1 expression increased mitochondrial intolerance in cardiomyocytes during HG-H/R injury and the AMPK-mTOR-autophagy signalling is a key mechanism for protecting mitochondrial function and reducing cardiomyocyte apoptosis. Collectively, dapagliflozin exerted protective effects on the cardiomyocytes under HG-H/R conditions. Dapagliflozin attenuated myocardial HG-H/R injury by activating AMPK/mTOR-OPA1-mediated mitochondrial autophagy.

摘要

本研究研究了达格列净在高糖和缺氧/复氧（HG-H/R）条件下对 H9c2 心肌细胞功能的保护作用，并确定了潜在的分子机制。在HG-H/R条件下，达格列净降低了心肌细胞中乳酸脱氢酶和活性氧的水平，并伴随着caspase-3/9活性的降低。此外，Dapagliflozin 显着减少线粒体通透性转换孔开放并增加 ATP 含量，同时上调 OPA1 和自噬相关蛋白分子，并激活 HG-H/R 处理的心肌细胞中的 AMPK/mTOR 信号通路。OPA1敲低或化合物C治疗减弱了达格列净在HG-H/R条件下对心肌细胞的保护作用。OPA1 表达下调会增加 HG-H/R 损伤期间心肌细胞的线粒体不耐受性，而 AMPK-mTOR-自噬信号传导是保护线粒体功能和减少心肌细胞凋亡的关键机制。总的来说，达格列净在 HG-H/R 条件下对心肌细胞发挥保护作用。Dapagliflozin 通过激活 AMPK/mTOR-OPA1 介导的线粒体自噬来减轻心肌 HG-H/R 损伤。