Li Guangru, Liu Ruiqing, Peng Zeyan, Zhang Shengzheng, Sun Runjia, Wang Ziwei, Li Jing, Gao Yang, Xu Yang, Cui Jianlin, Liu Jie, Yan Jie, Cao Lei, Ren Shan, Chu Yushun, Feng Lifeng, Yang Liang, Shen Yanna, Qi Zhi
Department of Molecular Pharmacology, School of Medicine, Nankai University; Department of Cardiology, Beichen Hospital, Nankai University, Tianjin, 300071, China.
School of Medical Technology, Tianjin Medical University, Tianjin, 300203, China.
Theranostics. 2025 Mar 31;15(11):4989-5006. doi: 10.7150/thno.107367. eCollection 2025.
: Diabetic cardiomyopathy (DCM), a prevalent complication of diabetes, is a major cause of heart failure and death among patients with diabetes. However, the pathological mechanisms underlying the development of DCM remain unclear. This study aims to investigate the role and underlying mechanisms of caveolin-1 (CAV1) in DCM. : DCM model was established through intraperitoneal injection of streptozotocin in mice and through high-glucose (HG) treatment in neonatal rat ventricular myocytes (NRVMs). CAV1-knockout (CAV1-KO) and overexpression (by injecting adeno-associated virus 9 (AAV9) encoding CAV1) mice were utilized to explore the role of CAV1 in DCM. Nuclear factor erythroid 2-related factor 2 (NRF2)-KO and AAV9-NRF2 mice and ML385 (an NRF2 inhibitor) were used to investigate the effect of NRF2 on DCM. : CAV1 expression was significantly increased in the cardiac tissues of diabetic mice and HG-treated NRVMs. CAV1 deficiency significantly alleviated diabetes-induced myocardial hypertrophy, fibrosis, abnormal mitochondria, excessive reactive oxygen species production, and ferroptosis. Conversely, cardiac-specific overexpression of CAV1 exacerbated cardiac dysfunction and myocardial histological abnormalities caused by diabetes. Mechanistically, CAV1 directly bound to NRF2 and inhibited its nuclear translocation, reducing the transcription of glutamate cysteine ligase catalytic subunit (GCLC), accumulating excess peroxide, and inducing ferroptosis and myocardial injury. : CAV1 exacerbates the progression of DCM by suppressing the NRF2/GCLC pathway, suggesting that targeting CAV1 is a potential therapeutic approach for DCM.
糖尿病性心肌病（DCM）是糖尿病常见的并发症，是糖尿病患者心力衰竭和死亡的主要原因。然而，DCM发生发展的病理机制仍不清楚。本研究旨在探讨小窝蛋白-1（CAV1）在DCM中的作用及其潜在机制。
通过腹腔注射链脲佐菌素建立小鼠DCM模型，并通过高糖（HG）处理新生大鼠心室肌细胞（NRVMs）。利用CAV1基因敲除（CAV1-KO）和过表达（通过注射编码CAV1的腺相关病毒9（AAV9））小鼠来探究CAV1在DCM中的作用。利用核因子红细胞2相关因子2（NRF2）基因敲除小鼠、AAV9-NRF2小鼠以及ML385（一种NRF2抑制剂）来研究NRF2对DCM的影响。
在糖尿病小鼠的心脏组织和经HG处理的NRVMs中，CAV1表达显著增加。CAV1缺乏显著减轻了糖尿病诱导的心肌肥大、纤维化、线粒体异常、过量活性氧生成和铁死亡。相反，心脏特异性过表达CAV1加剧了糖尿病引起的心脏功能障碍和心肌组织学异常。机制上，CAV1直接与NRF2结合并抑制其核转位，减少谷氨酸半胱氨酸连接酶催化亚基（GCLC）的转录，积累过量过氧化物，诱导铁死亡和心肌损伤。
CAV1通过抑制NRF2/GCLC途径加剧DCM的进展，提示靶向CAV1是DCM一种潜在的治疗方法。
