2. Academic Validation
  3. USP7 promotes cardiometabolic disorders and mitochondrial homeostasis dysfunction in diabetic mice via stabilizing PGC1β

USP7 promotes cardiometabolic disorders and mitochondrial homeostasis dysfunction in diabetic mice via stabilizing PGC1β

  • Pharmacol Res. 2024 Jul:205:107235. doi: 10.1016/j.phrs.2024.107235.
Meiling Yan 1,  Liyan Su 2,  Kaile Wu 3,  Yu Mei 3,  Zhou Liu 3,  Yifan Chen 3,  Wenru Zeng 3,  Yang Xiao 3,  Jingfei Zhang 3,  Guida Cai 3,  Yunlong Bai 4
Affiliations

Affiliations

  • 1 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. Electronic address: yanmeiling0122@gdpu.edu.cn.
  • 2 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.
  • 3 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.
  • 4 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; Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Chronic Disease Research Institute, Heilongjiang Academy of Medical Sciences, Harbin, China. Electronic address: baiyunlong@ems.hrbmu.edu.cn.
PMID: 38815879 DOI: 10.1016/j.phrs.2024.107235
Abstract

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.

Keywords

Cardio-metabolism; Diabetic cardiomyopathy; Mitochondrial homeostasis; PGC1β/PPARα; USP7.

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