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Punicalagin Protects Against Diabetic Cardiomyopathy by Promoting Opa1-Mediated Mitochondrial Fusion via Regulating PTP1B-Stat3 Pathway.

PMID: 33906428 (view PubMed database entry)
DOI: 10.1089/ars.2020.8248 (read at publisher's website )

Feng Fu, Chaoyang Liu, Rui Shi, Man Li, Min Zhang, Yanyan Du, Qiaojuan Wang, Jun Li, Guoen Wang, Jianming Pei, Mingge Ding,

<b><i>Aims:</i></b> This study aims to explore the efficacy of punicalagin (PG) on diabetic cardiomyopathy (DCM), with a specific focus on the mechanisms underlying the effects of PG on mitochondrial fusion/fission dynamics. <b><i>Results:</i></b> Cardiac structural and functional abnormalities were ameliorated in diabetic rats receiving PG administration as evidenced by increased ejection fraction, and attenuated myocardial fibrosis and hypertrophy. PG enhanced mitochondrial function and inhibited mitochondria-derived oxidative stress by promoting Opa1-mediated mitochondrial fusion. The benefits of PG could be abrogated by knockdown of Opa1 <i>in vivo</i> and <i>in vitro</i>. 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 PG-induced Opa1-mediated mitochondrial fusion. Moreover, pharmmapper screening and molecular docking studies revealed that PG embedded into the activity pocket of PTP1B and inhibited the activity of PTP1B. Overexpression of PTP1B blocked the promoting effect of PG on Stat3 phosphorylation and Opa1-mediated mitochondrial fusion, whereas knockdown of PTP1B mimicked the benefits of PG in high-glucose-treated cardiomyocytes. <b><i>Innovation:</i></b> Our study is the first to identify PG as a novel mitochondrial fusion promoter against hyperglycemia-induced mitochondrial oxidative injury and cardiomyopathy by upregulating Opa1 <i>via</i> regulating PTP1B-Stat3 pathway. <b><i>Conclusion:</i></b> PG protects against DCM by promoting Opa1-mediated mitochondrial fusion, a process in which PG interacts with PTP1B and inhibits its activity, which in turn increases Stat3 phosphorylation and then enhances the transcriptional expression of Opa1. These results suggest that PG might be a promising new therapeutic approach against diabetic cardiac complication.

Antioxid Redox Signal (Antioxidants & redox signaling)
[2021, :]

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