He Minjie, Yang Yongheng, He Xing, Lei Rong, Liu Hong, Yang Mei
Health Management Centre, The First Affiliated Hospital of Kunming Medical University, Kunming, 650034, Yunnan, China.
Department of Thyroid & Breast Surgery, Dali Bai Autonomous Prefecture People's Hospital, Dali, 671000, Yunnan, China.
In Vitro Cell Dev Biol Anim. 2025 Feb;61(2):135-148. doi: 10.1007/s11626-024-00995-z. Epub 2025 Jan 21.
Melatonin (MEL), functioning as a circulating hormone, is important for the regulation of ferroptosis in different health scenarios and acts as a crucial antioxidant in cardiovascular diseases. However, its specific function in ferroptosis related to myocardial ischemia-reperfusion injury (MIRI) remains to be fully elucidated. In our research, we utilized a rat model of MIRI induced by coronary artery ligation, along with a cell model subjected to hypoxia/reoxygenation (H/R). We evaluated relevant genes and proteins by real-time fluorescent quantitative PCR and Western blot analysis. To evaluate myocardial tissue damage and cell injury, we employed cell counting kit-8 assays, flow cytometry, hematoxylin-eosin staining, and 2,3,5-triphenyltetrazolium chloride staining techniques. Our results show that administering MEL notably reduces the concentrations of cTnT, CK-MB, and lactate dehydrogenase in the serum of MIRI rats, mitigates the extent of myocardial infarction, improves the recovery of pathological conditions in myocardial tissues, and reduces the concentrations of Fe, malondialdehyde (MDA), and reactive oxygen species (ROS) in the myocardial tissue, while also promoting increased glutathione levels. Moreover, MEL can also restore the reduced viability of H9C2 cells caused by H/R or ferroptosis inducers (RSL3), reduce the cellular content of Fe, MDA, and ROS, and inhibit ferroptosis. Mechanistically, MEL promotes the expression of GPX4 by downregulating the expression of ATF3, thereby inhibiting ferroptosis in cardiomyocytes and ultimately alleviating the process of MIRI. Our study demonstrates that MEL ameliorates MIRI by inhibiting ferroptosis.
褪黑素（MEL）作为一种循环激素，在不同健康状况下对铁死亡的调节起着重要作用，并且在心血管疾病中充当关键的抗氧化剂。然而，其在与心肌缺血再灌注损伤（MIRI）相关的铁死亡中的具体功能仍有待充分阐明。在我们的研究中，我们利用冠状动脉结扎诱导的MIRI大鼠模型以及缺氧/复氧（H/R）细胞模型。我们通过实时荧光定量PCR和蛋白质免疫印迹分析评估相关基因和蛋白质。为了评估心肌组织损伤和细胞损伤，我们采用了细胞计数试剂盒-8检测、流式细胞术、苏木精-伊红染色和2,3,5-三苯基氯化四氮唑染色技术。我们的结果表明，给予MEL可显著降低MIRI大鼠血清中肌钙蛋白T（cTnT）、肌酸激酶同工酶（CK-MB）和乳酸脱氢酶的浓度，减轻心肌梗死程度，改善心肌组织病理状况的恢复，并降低心肌组织中铁、丙二醛（MDA）和活性氧（ROS）的浓度，同时还促进谷胱甘肽水平升高。此外，MEL还可以恢复由H/R或铁死亡诱导剂（RSL3）导致的H9C2细胞活力降低，减少细胞内铁、MDA和ROS的含量，并抑制铁死亡。从机制上讲，MEL通过下调激活转录因子3（ATF3）的表达来促进谷胱甘肽过氧化物酶4（GPX4）的表达，从而抑制心肌细胞中的铁死亡，最终减轻MIRI的进程。我们的研究表明，MEL通过抑制铁死亡来改善MIRI。
