Xu Chenxi, Wu Mengni, Yu Wei, Xie De, Wang Qiang, Chen Binyang, Xi Yuemei, Yu Linqian, Yan Yunbo, Yamamoto Tetsuya, Koyama Hidenori, Zhao Hong, Cheng Jidong
Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, China.
Institute of Metabolism and Cell Death, Helmholtz Munich, 85764 Neuherberg, Bavaria, Germany.
Antioxid Redox Signal. 2024 Dec;41(16-18):1134-1149. doi: 10.1089/ars.2023.0473. Epub 2024 Aug 28.
High uric acid (HUA), as a pro-oxidant, plays a significant role in the pathophysiology of cardiovascular disease. Studies have indicated that elevated uric acid levels can adversely affect cardiovascular health. Nevertheless, the impact of hyperuricemia on cardiomyopathy remains uncertain. Further research is needed to elucidate the relationship between HUA and cardiomyopathy, shedding light on its potential implications for heart health. We demonstrated that uricase knockout (Uox-KO) mice accelerated the development of cardiomyopathy, causing significantly impaired cardiac function and myocardial fibrosis. Meanwhile, the mitochondrial morphology was destroyed, the lipid peroxidation products increased in number and the antioxidant function was weakened. In addition, we evaluated the effects of ferrostatin-1 (Fer-1), the ferroptosis inhibitor. Myocardial damage can be reversed by the Fer-1 treatment caused by HUA combined with doxorubicin (DOX) treatment. Benzbromarone, a uric acid-lowering drug, decreases myocardial fibrosis, and ferroptosis by alleviating hyperuricemia in Uox-KO mice by DOX administration. In vitro, we observed that the activity of cardiomyocytes treated with HUA combined with DOX decreased significantly, and lipid reactive oxygen species (ROS) increased significantly. Afterward, we demonstrated that HUA can promote oxidative stress in DOX, characterized by increased mitochondrial ROS, and downregulate protein levels of glutathione peroxidase 4 (GPX4). -acetyl-l-cysteine, an antioxidant, inhibits the process by which HUA promotes DOX-induced ferroptosis by increasing the GPX4 expression. We verified that HUA can exacerbate myocardial damage. This has clinical implications for the treatment of cardiac damage in patients with hyperuricemia. Our data suggested that HUA promotes the cardiomyopathy. HUA promotes DOX-induced ferroptosis by increasing oxidative stress and downregulating GPX4. 41, 1134-1149.
高尿酸（HUA）作为一种促氧化剂，在心血管疾病的病理生理学中起着重要作用。研究表明，尿酸水平升高会对心血管健康产生不利影响。然而，高尿酸血症对心肌病的影响仍不确定。需要进一步研究以阐明HUA与心肌病之间的关系，从而揭示其对心脏健康的潜在影响。我们证明，尿酸酶基因敲除（Uox-KO）小鼠加速了心肌病的发展，导致心脏功能显著受损和心肌纤维化。同时，线粒体形态遭到破坏，脂质过氧化产物数量增加，抗氧化功能减弱。此外，我们评估了铁死亡抑制剂铁抑素-1（Fer-1）的作用。Fer-1治疗可逆转由HUA联合阿霉素（DOX）治疗引起的心肌损伤。苯溴马隆是一种降尿酸药物，通过对Uox-KO小鼠给予DOX来减轻高尿酸血症，从而减少心肌纤维化和铁死亡。在体外，我们观察到HUA联合DOX处理的心肌细胞活性显著降低，脂质活性氧（ROS）显著增加。随后，我们证明HUA可促进DOX中的氧化应激，表现为线粒体ROS增加，并下调谷胱甘肽过氧化物酶4（GPX4）的蛋白水平。抗氧化剂N-乙酰半胱氨酸通过增加GPX4表达来抑制HUA促进DOX诱导的铁死亡的过程。我们证实HUA会加重心肌损伤。这对高尿酸血症患者心脏损伤的治疗具有临床意义。我们的数据表明HUA会促进心肌病。HUA通过增加氧化应激和下调GPX4来促进DOX诱导的铁死亡。41, 1134 - 1149。
