Punicalagin Promotes Mitochondrial Fusion and Alleviates Diabetic Cardiomyopathy via Regulating PTP1B-Stat3-Opa1 Pathway

This study aims to explore the efficacy of punicalagin on diabetic cardiomyopathy, with a specific focus on the mechanisms underlying the effects of punicalagin on mitochondrial fusion/fission dynamics. Diabetes was induced by a single intraperitoneal injection of streptozotocin intraperitoneally in Sprague-Dawley rats. Cardiac structural and functional abnormalities were ameliorated in diabetic rats receiving punicalagin administration as evidenced by increased ejection fraction and attenuated myocardial fibrosis and hypertrophy. Punicalagin promoted mitochondrial fusion and enhanced mitochondrial function in both diabetic hearts and high glucose-treated cardiomyocytes. Punicalagin-induced increases in Opa1 expression were responsible for the above mitochondrial enhancements, and these changes could be blocked by knockdown of Opa1. Inhibitor screening and chromatin immunoprecipitation analysis showed that Stat3 directly regulated the transcriptional expression of Opa1 by binding to its promoter and was responsible for punicalagin-induced Opa1-mediated mitochondrial fusion. Moreover, pharmmapper screening and molecular docking studies revealed that punicalagin embedded into the activity pocket of PTP1B and inhibited the activity of PTP1B. Overexpression of PTP1B blocked the promoting effect of punicalagin on Stat3 phosphorylation and Opa1-mediated mitochondrial fusion. Collectively, our study has provided the first evidence that punicalagin protects against diabetic cardiomyopathy and uncovered the precise mechanisms on how punicalagin promotes Opa1-mediated mitochondrial fusion under hyperglycemic condition, a process in which punicalagin interacts with PTP1B and inhibits its activity that in turn increasing Stat3 phosphorylation and then enhancing the transcriptional expression of Opa1. Disclosure M. Ding: None. M. Li: None. F. Fu: None. C. Liu: None. Funding National Natural Science Foundation of China (81970316, 82070387)