Celastrol confers ferroptosis resistance via AKT/GSK3β signaling in high-fat diet-induced cardiac injury
Celastrol confers ferroptosis resistance via AKT/GSK3β signaling in high-fat diet-induced cardiac injury
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Celastrol通过AKT/GSK3β信号传导在高脂肪饮食诱导的心脏损伤中赋予铁凋亡抵抗
DOI：
10.1016/j.freeradbiomed.2023.03.004
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发表时间：
2023-03-12
影响因子：
7.4
通讯作者：
Shao, Yongfeng
中科院分区：
文献类型：
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作者：
Bian, Jinhui;Ding, Yi;Shao, Yongfeng
肥胖性心功能障碍是一种与高膳食脂肪摄入量相关的严重全球性疾病，其发病机制包括炎症、氧化应激和铁下垂。雷公藤红素(CEL)是从雷公藤中分离得到的一种生物活性化合物，对心血管疾病具有保护作用。本研究旨在探讨CEL在肥胖引起的铁性下垂和心脏损伤中的作用。我们发现，CEL减轻了棕榈酸(PA)诱导的铁下垂，表现出LDH、CK-MB、Ptgs2和脂质过氧化水平的降低。加入LY294002和LiCl后，Cel通过增加AKT/GSK38的磷酸化、降低脂质过氧化水平和线粒体ROS而发挥其保护作用。升高的p-GSK38可抑制铁下垂，减轻肥胖小鼠的左心室收缩功能障碍，CEL可降低线粒体ROS。此外，线粒体异常包括心肌肿胀和变形，CEL缓解了这一异常。总之，我们的结果表明，在HFD条件下，CEL对铁下垂的抵抗以AKT/GSK38信号为靶点，这为肥胖引起的心脏损伤提供了新的治疗策略。
Obesity-induced cardiac dysfunction is a severe global disease associated with high dietary fat intake, and its pathogenesis includes inflammation, oxidative stress, and ferroptosis. Celastrol (Cel) is a bioactive compound isolated from the herb Tripterygium wilfordii, which has a protective influence on cardiovascular diseases. In this study, the role of Cel in obesity-induced ferroptosis and cardiac injury was investigated. We found that Cel alleviated ferroptosis induced by Palmitic acid (PA), exhibiting a decrease in the LDH, CK-MB, Ptgs2, and Lipid Peroxidation levels. After cardiomyocytes were treated with additional LY294002 and LiCl, Cel exerted its protective effect through increased AKT/GSK38 phosphorylation and decreased level of lipid peroxidation and Mitochondrial ROS. The systolic left ventricle (LV) dysfunction of obese mice was alleviated via ferroptosis in-hibition by elevated p-GSK38 and decreased Mitochondrial ROS under Cel treatment. Moreover, mitochondrial anomalies included swelling and distortion in the myocardium which was relieved with Cel. In conclusion, our results demonstrate that ferroptosis resistance with Cel under HFD conditions targets AKT/GSK38 signaling, which provides novel therapeutic strategies in obesity-induced cardiac injury.