Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou, China; Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou, China; Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China.
Pharmacol Res. 2024 Jul;205:107235. doi: 10.1016/j.phrs.2024.107235. Epub 2024 May 28.
Diabetic cardiomyopathy (DCM) is a major complication of diabetes and is characterized by left ventricular dysfunction. Currently, there is a lack of effective treatments for DCM. Ubiquitin-specific protease 7 (USP7) plays a key role in various diseases. However, whether USP7 is involved in DCM has not been established. In this study, we demonstrated that USP7 was upregulated in diabetic mouse hearts and NMCMs co-treated with HG+PA or H9c2 cells treated with PA. Abnormalities in diabetic heart morphology and function were reversed by USP7 silencing through conditional gene knockout or chemical inhibition. Proteomic analysis coupled with biochemical validation confirmed that PCG1β was one of the direct protein substrates of USP7 and aggravated myocardial damage through coactivation of the PPARα signaling pathway. USP7 silencing restored the expression of fatty acid metabolism-related proteins and restored mitochondrial homeostasis by inhibiting mitochondrial fission and promoting fusion events. Similar effects were also observed in vitro. Our data demonstrated that USP7 promoted cardiometabolic metabolism disorders and mitochondrial homeostasis dysfunction via stabilizing PCG1β and suggested that silencing USP7 may be a therapeutic strategy for DCM.
糖尿病心肌病（DCM）是糖尿病的一种主要并发症，其特征为左心室功能障碍。目前，DCM 缺乏有效的治疗方法。泛素特异性蛋白酶 7（USP7）在各种疾病中发挥关键作用。然而，USP7 是否参与 DCM 尚未确定。在本研究中，我们证明 USP7 在糖尿病小鼠心脏和高糖+棕榈酸（HG+PA）共处理的 NMCM 或经棕榈酸（PA）处理的 H9c2 细胞中上调。通过条件性基因敲除或化学抑制使 USP7 沉默，可逆转糖尿病心脏形态和功能的异常。蛋白质组学分析结合生化验证证实，PCG1β 是 USP7 的直接蛋白底物之一，通过共激活过氧化物酶体增殖物激活受体 α（PPARα）信号通路加重心肌损伤。USP7 沉默通过抑制线粒体分裂和促进融合事件恢复脂肪酸代谢相关蛋白的表达，恢复线粒体动态平衡。在体外也观察到了类似的效果。我们的数据表明，USP7 通过稳定 PCG1β 促进心脏代谢代谢紊乱和线粒体动态平衡功能障碍，并提示沉默 USP7 可能是 DCM 的一种治疗策略。
