Chen Yuqiong, Guan Bo, Lu Jian, Yan Xiaopei, Huang Chao, Qiu Yuli, Li Xinyan, Sun Xiangyu, Chen Lin, Li Wei, Mao Wenjun, Sun Zhongqi, Xu Bin, Li Su, Chen Chao
Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Nanjing, China.
Department of Geriatrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Nanjing, China.
Front Cell Dev Biol. 2025 Jul 22;13:1623846. doi: 10.3389/fcell.2025.1623846. eCollection 2025.
This study aims to investigate the benefits of gypensapogenin I (GI) on myocardial ischemia-reperfusion injury (MIRI) and the underlying mechanisms.
An MIRI model was established by ligating the anterior descending coronary artery (LAD) followed by blood flow restoration in mice. Cardiac dysfunction and myocardial infarction size were evaluated by echocardiography and triphenyltetrazolium chloride (TTC) staining. PANoptosis, ferroptosis, and mitochondrial redox state were examined by immunofluorescence, Western blotting, and an ELISA kit. In addition, molecular and biochemical methods were applied to illustrate the exact mechanisms of GI on MIRI.
GI pretreatment alleviated cellular oxidative stress, inhibited PANoptosis and ferroptosis, reduced myocardial infarction area, and improved cardiac function during MIRI. Further results revealed that mitochondrial biogenesis and the anti-oxidative system were impaired in mice suffering from MIRI, and these effects were significantly alleviated by GI treatment via downregulation of the NADPH oxidase 2 (NOX2) level. Moreover, NOX2 promoted mitochondrial dysfunction by suppressing the AMP-activated protein kinase (AMPK)-PGC-1α-Sirt3 signaling pathway. In addition, the NOX2 activator exacerbated oxidative damage and offset all the beneficial effects of GI on mitochondrial function, PANoptosis, and ferroptosis. Meanwhile, reinforced AMPK phosphorylation by GI or AMPK activator (5-aminoimidazole-4-carboxamide ribonucleotide, AICAR) maintained the mitochondrial redox state and biogenesis and suppressed PANoptosis and ferroptosis.
GI pretreatment protected the cardiomyocytes from MIRI-induced PANoptosis and ferroptosis by maintaining the mitochondrial redox state and biogenesis through the modulation of the NOX2/AMPK signaling pathway. Our findings indicate that GI pretreatment could be a promising therapeutic agent for MIRI treatment.
本研究旨在探讨绞股蓝皂苷I（GI）对心肌缺血再灌注损伤（MIRI）的益处及其潜在机制。
通过结扎小鼠冠状动脉前降支（LAD）并随后恢复血流来建立MIRI模型。通过超声心动图和氯化三苯基四氮唑（TTC）染色评估心脏功能障碍和心肌梗死面积。通过免疫荧光、蛋白质印迹和ELISA试剂盒检测泛凋亡、铁死亡和线粒体氧化还原状态。此外，应用分子和生化方法阐明GI对MIRI的确切作用机制。
GI预处理减轻了细胞氧化应激，抑制了泛凋亡和铁死亡，减少了心肌梗死面积，并改善了MIRI期间的心脏功能。进一步的结果表明，MIRI小鼠的线粒体生物合成和抗氧化系统受损，而GI治疗通过下调NADPH氧化酶2（NOX2）水平显著减轻了这些影响。此外，NOX2通过抑制AMP激活的蛋白激酶（AMPK）-PGC-1α-Sirt3信号通路促进线粒体功能障碍。此外，NOX2激活剂加剧了氧化损伤并抵消了GI对线粒体功能、泛凋亡和铁死亡的所有有益作用。同时，GI或AMPK激活剂（5-氨基咪唑-4-甲酰胺核糖核苷酸，AICAR）增强的AMPK磷酸化维持了线粒体氧化还原状态和生物合成，并抑制了泛凋亡和铁死亡。
GI预处理通过调节NOX2/AMPK信号通路维持线粒体氧化还原状态和生物合成，从而保护心肌细胞免受MIRI诱导的泛凋亡和铁死亡。我们的研究结果表明，GI预处理可能是一种有前途的MIRI治疗药物。
