Zhang Xiaoliang, Zhou Chunbei, Chen Guozhu, Li Yuanzhu, Liu Xiaorui, Luo Suxin
Development of Cardiovascular, The Beibei Affiliated Hospital of Chongqing Medical University, Chongqing 400700, China.
Chongqing Municipal Center for Disease Control and Prevention, Chongqing 400707, China; Department of Disease Prevention and Control, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University (Third Military Medical University), Chongqing 400042,China.
Life Sci. 2025 Sep 15;377:123798. doi: 10.1016/j.lfs.2025.123798. Epub 2025 Jun 4.
Myocardial infarction (MI) results in mitochondrial dysfunction and metabolic imbalance, ultimately causing cellular injury and impaired cardiac function. Dapagliflozin (DAPA) has been shown to reduce cardiovascular mortality; however, the underlying mechanisms by which it confers cardioprotection in MI remain incompletely understood.
To explore the protective role of DAPA, an oxygen-glucose deprivation (OGD) model was established in H9c2 cardiomyoblasts to assess its effects on cell proliferation, apoptosis, metabolism, and mitochondrial function. A series of molecular assays, including qRT-PCR, Western blotting, chromatin immunoprecipitation (ChIP), dual-luciferase reporter analysis, and rescue experiments, were performed to elucidate the involvement of HIF-1α, FOXO3, and STC1 in DAPA-mediated responses. In vivo, the cardioprotective effects of DAPA were validated using a rat model of MI.
DAPA promoted proliferation, inhibited apoptosis, and restored glucose uptake, ATP generation, and mitochondrial activity in OGD-treated H9c2 cells by modulating the JNK signaling pathway, promoting FOXO3 degradation, and engaging the HIF-1α-STC1 axis. In MI rats, DAPA significantly reduced infarct size, improved cardiac function, and alleviated myocardial fibrosis and apoptosis. Rescue experiments further confirmed that overexpression of STC1 potentiated DAPA's effects, whereas STC1 knockdown attenuated them.
These findings indicate that the HIF-1α-FOXO3-STC1 pathway plays a central role in the cardioprotective mechanisms of DAPA. By modulating the MAPK-FOXO3-STC1 and HIF-1α-STC1 signaling cascades, DAPA improves mitochondrial function and metabolic homeostasis, supporting its therapeutic potential in the treatment of MI.
心肌梗死（MI）会导致线粒体功能障碍和代谢失衡，最终引起细胞损伤和心脏功能受损。达格列净（DAPA）已被证明可降低心血管疾病死亡率；然而，其在心肌梗死中发挥心脏保护作用的潜在机制仍未完全明确。
为探究达格列净的保护作用，在H9c2心肌成纤维细胞中建立氧糖剥夺（OGD）模型，以评估其对细胞增殖、凋亡、代谢和线粒体功能的影响。进行了一系列分子检测，包括qRT-PCR、蛋白质免疫印迹、染色质免疫沉淀（ChIP）、双荧光素酶报告基因分析和挽救实验，以阐明缺氧诱导因子-1α（HIF-1α）、叉头框蛋白O3（FOXO3）和抑癌素M（STC1）在达格列净介导的反应中的作用。在体内，使用心肌梗死大鼠模型验证了达格列净的心脏保护作用。
达格列净通过调节JNK信号通路、促进FOXO3降解和激活HIF-1α-STC1轴，促进了OGD处理的H9c2细胞的增殖，抑制了凋亡，并恢复了葡萄糖摄取、ATP生成和线粒体活性。在心肌梗死大鼠中，达格列净显著减小梗死面积，改善心脏功能，并减轻心肌纤维化和凋亡。挽救实验进一步证实，STC1的过表达增强了达格列净的作用，而STC1的敲低则减弱了这些作用。
这些发现表明，HIF-1α-FOXO3-STC1通路在达格列净的心脏保护机制中起核心作用。通过调节丝裂原活化蛋白激酶-FOXO3-STC1和HIF-1α-STC1信号级联反应，达格列净改善了线粒体功能和代谢稳态，支持了其在心肌梗死治疗中的治疗潜力。
