Ding Jun, Wang Bi-Ying, Yang Yu-Fan, Kuai Ling-Yu, Wan Jing-Jie, Zhang Mian, Xia Hai-Yan, Wang Yao, Zheng Zhong, Meng Xiao-Wen, Peng Ke, Ji Fu-Hai
Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China.
Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, People's Republic of China.
Drug Des Devel Ther. 2024 Dec 18;18:6115-6132. doi: 10.2147/DDDT.S480514. eCollection 2024.
Ciprofol is a novel intravenous anesthetic that has been increasingly used in clinical anesthesia and sedation. Studies suggested that ciprofol reduced oxidative stress and inflammatory responses to alleviate cerebral ischemia/reperfusion (I/R) injury, but whether ciprofol protects the heart against I/R injury and the mechanisms are unknown. Herein, we assessed the effects of ciprofol on ferroptosis during myocardial I/R injury.
Experimental models of myocardial I/R injury in mice (ischemia for 30 min and reperfusion for 24 h) and hypoxia/reoxygenation (H/R) injury in H9c2 cardiomyocytes (hypoxia for 6 h followed by 6 h of reoxygenation) were established. Ciprofol was used prior to ischemia or hypoxia. Echocardiography, myocardial TTC staining, HE staining, DAB-enhanced Perl's staining, transmission electron microscopy, FerroOrange staining, Liperfluo staining, JC-1 staining, Rhodamine-123 staining, DCFH-DA staining, and Western blot were performed. Cell viability, serum cardiac enzymes, and oxidative- and ferroptosis-related biomarkers were measured. HIF-1α siRNA transfection and the specific inhibitor BAY87-2243 were utilized for mechanistic investigation.
Ciprofol treatment reduced myocardial infarct area and myocardium damage, alleviated oxidative stress and mitochondrial injury, suppressed Fe accumulation and ferroptosis, and improved cardiac function in mice with myocardial I/R injury. Ciprofol also increased cell viability, attenuated mitochondrial damage, and reduced intracellular Fe and lipid peroxidation in cardiomyocytes with H/R injury. Ciprofol enhanced the protein expression of HIF-1α and GPX4 and reduced the expression of ACSL4. Specifically, the protective effects of ciprofol against I/R or H/R injury were abolished by downregulating the expression of HIF-1α using siRNA transfection or the inhibitor BAY87-2243.
Ciprofol ameliorated myocardial I/R injury in mice and H/R injury in cardiomyocytes by inhibiting ferroptosis via the upregulation of HIF-1α expression.
环泊酚是一种新型静脉麻醉药，已越来越多地应用于临床麻醉和镇静。研究表明，环泊酚可降低氧化应激和炎症反应，以减轻脑缺血/再灌注（I/R）损伤，但环泊酚是否能保护心脏免受I/R损伤及其机制尚不清楚。在此，我们评估了环泊酚在心肌I/R损伤过程中对铁死亡的影响。
建立小鼠心肌I/R损伤（缺血30分钟，再灌注24小时）和H9c2心肌细胞缺氧/复氧（H/R）损伤（缺氧6小时，随后复氧6小时）的实验模型。在缺血或缺氧前使用环泊酚。进行超声心动图、心肌TTC染色、HE染色、DAB增强的Perl染色、透射电子显微镜、FerroOrange染色、Liperfluo染色、JC-1染色、罗丹明-123染色、DCFH-DA染色和蛋白质印迹分析。检测细胞活力、血清心肌酶以及与氧化和铁死亡相关的生物标志物。利用HIF-1α siRNA转染和特异性抑制剂BAY87-2243进行机制研究。
环泊酚治疗可减少心肌梗死面积和心肌损伤，减轻氧化应激和线粒体损伤，抑制铁积累和铁死亡，并改善心肌I/R损伤小鼠的心脏功能。环泊酚还可提高H/R损伤心肌细胞的细胞活力，减轻线粒体损伤，并减少细胞内铁和脂质过氧化。环泊酚增强了HIF-1α和GPX4的蛋白表达，并降低了ACSL4的表达。具体而言，通过siRNA转染或抑制剂BAY87-2243下调HIF-1α的表达，可消除环泊酚对I/R或H/R损伤的保护作用。
环泊酚通过上调HIF-1α表达抑制铁死亡，从而改善小鼠心肌I/R损伤和心肌细胞H/R损伤。
