Curcumin pretreatment attenuates myocardial ischemia/reperfusion injury by inhibiting ferroptosis, autophagy and apoptosis via HES1.

IF 5.7 3区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
International journal of molecular medicine Pub Date : 2024-12-01 Epub Date: 2024-10-04 DOI:10.3892/ijmm.2024.5434
Yong Yuan, Huang Huang, Tie Hu, Chenchao Zou, Yamei Qiao, Ming Fang, Jichun Liu, Songqing Lai
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引用次数: 0

Abstract

The early restoration of hemodynamics/reperfusion in acute myocardial infarction (AMI) is an effective therapeutic strategy to reduce sudden death and improve patient prognosis. However, reperfusion induces additional cardiomyocyte damage and cardiac tissue dysfunction. In this context, turmeric‑derived curcumin (Cur) has been shown to exhibit a protective effect against myocardial ischemia/reperfusion injury (I/RI). The molecular mechanism of its activity, however, remains unclear. The current study investigated the protective effect of Cur and its molecular mechanism via in vitro experiments. The Cell Counting Kit‑8 and lactate dehydrogenase (LDH) assay kit were used to assess the cell viability and cytotoxicity. The contents of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase, glutathione (GSH)/glutathione disulfide (GSSG), total iron, ferrous iron, caspase‑3 and reactive oxygen species (ROS) were measured using an appropriate kit. Western blotting was used to detect the expression of relevant proteins. The levels of apoptosis, mitochondrial permeability transition pore (MPTP) opening, and mitochondrial membrane potential (MMP) were detected by flow cytometry. The study findings indicated that anoxia/reoxygenation (A/R) injury significantly decreased cell viability, increased in LDH and caspase‑3 activities, induced ferroptosis, increased apoptosis and overactivated autophagy. However, pretreatment with Cur or ferrostatin‑1 (Fer‑1, a ferroptosis inhibitor) significantly increased A/R‑reduced cell viability, SOD, glutathione peroxidase activity, GSH/GSSH ratio and HES1 and glutathione peroxidase 4 protein expression; attenuated A/R‑induced LDH, MDA, total iron, ferrous iron, prostaglandin‑endoperoxide synthase 2 protein expression and prevented ROS overproduction and MMP loss. In addition, Cur inhibited caspase‑3 activity, upregulated the Bcl‑2/Bax ratio, reduced apoptotic cell number and inhibited MPTP over‑opening. Furthermore, Cur increased P62, LC3II/I, NDUFB8 and UQCRC2 expression and upregulated the p‑AMPK/AMPK ratio. However, erastin (a ferroptosis activator), pAD/HES1‑short hairpin RNA, rapamycin (an autophagy activator) and Compound C (an AMPK inhibitor) blocked the protective effect of Cur. In conclusion, Cur pretreatment inhibited ferroptosis, autophagy overactivation and oxidative stress; improved mitochondrial dysfunction; maintained energy homeostasis; attenuated apoptosis; and ultimately protected the myocardium from A/R injury via increased HES1 expression.

姜黄素通过 HES1 抑制铁凋亡、自噬和细胞凋亡,从而减轻心肌缺血再灌注损伤。
急性心肌梗死(AMI)患者早期恢复血流动力学/再灌注是减少猝死和改善患者预后的有效治疗策略。然而,再灌注会诱发额外的心肌细胞损伤和心脏组织功能障碍。在这种情况下,姜黄提取物姜黄素(Cur)已被证明对心肌缺血/再灌注损伤(I/RI)具有保护作用。然而,其活性的分子机制仍不清楚。本研究通过体外实验研究了 Cur 的保护作用及其分子机制。细胞计数试剂盒-8 和乳酸脱氢酶(LDH)检测试剂盒用于评估细胞活力和细胞毒性。使用适当的试剂盒检测丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶、谷胱甘肽(GSH)/二硫化谷胱甘肽(GSSG)、总铁、亚铁、Caspase-3 和活性氧(ROS)的含量。采用 Western 印迹法检测相关蛋白质的表达。流式细胞术检测了细胞凋亡、线粒体通透性转换孔(MPTP)开放和线粒体膜电位(MMP)的水平。研究结果表明,缺氧/复氧(A/R)损伤会明显降低细胞活力、增加 LDH 和 caspase-3 活性、诱导铁变态反应、增加细胞凋亡和过度激活自噬。然而,用 Cur 或铁前列素-1(Fer-1,一种铁变态反应抑制剂)预处理可明显提高 A/R 降低的细胞活力、SOD、谷胱甘肽过氧化物酶活性、GSH/GSSH 比率以及 HES1 和谷胱甘肽过氧化物酶 4 蛋白表达;减轻 A/R 诱导的 LDH、MDA、总铁、亚铁、前列腺素内过氧化物合成酶 2 蛋白表达,并防止 ROS 过度产生和 MMP 损失。此外,Cur 还能抑制 caspase-3 活性,上调 Bcl-2/Bax 比率,减少凋亡细胞数量,抑制 MPTP 过度开放。此外,Cur 还能增加 P62、LC3II/I、NDUFB8 和 UQCRC2 的表达,并上调 p-AMPK/AMPK 比率。然而,erastin(一种铁突变激活剂)、pAD/HES1-短发夹核糖核酸、雷帕霉素(一种自噬激活剂)和化合物 C(一种 AMPK 抑制剂)阻断了 Cur 的保护作用。总之,Cur 预处理抑制了铁变态反应、自噬过度激活和氧化应激;改善了线粒体功能障碍;维持了能量平衡;减轻了细胞凋亡;并最终通过增加 HES1 的表达保护心肌免受 A/R 损伤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International journal of molecular medicine
International journal of molecular medicine 医学-医学:研究与实验
CiteScore
12.30
自引率
0.00%
发文量
124
审稿时长
3 months
期刊介绍: The main aim of Spandidos Publications is to facilitate scientific communication in a clear, concise and objective manner, while striving to provide prompt publication of original works of high quality. The journals largely concentrate on molecular and experimental medicine, oncology, clinical and experimental cancer treatment and biomedical research. All journals published by Spandidos Publications Ltd. maintain the highest standards of quality, and the members of their Editorial Boards are world-renowned scientists.
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