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Iranian Journal of Basic Medical Sciences، جلد ۲۸، شماره ۱۱، صفحات ۱۵۶۳-۱۵۷۴
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عنوان انگلیسی Dapagliflozin improves diabetic cardiomyopathy by suppressing the STAT3-YY1 signaling axis in cardiac fibroblasts
چکیده انگلیسی مقاله Objective(s): Cardiac fibroblast (CF) proliferation and activation drive cardiac fibrosis and heart failure. Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, ameliorates diabetic cardiomyopathy (DCM). We investigated whether DAPA exerts anti-fibrotic and cardioprotective effects on DCM by directly suppressing CF proliferation and activation independent of SGLT2 inhibition. Materials and Methods: CFs were isolated from mouse hearts. Mouse cardiac function and fibrosis were investigated using histological analysis, western blotting, and echocardiography. Additionally, genetic loss-of-function studies were conducted in vitro by small interfering RNA silencing and in vivo by lentivirus-mediated gene knockdown. Results: Compared with high-glucose-treated neonatal rat CFs, genetic loss-of-function of signal transducer and activator of transcription 3 (STAT3) or pretreatment with DAPA dramatically inhibited STAT3 phosphorylation and Yin Yang 1 (YY1) nuclear translocation, alleviated CF proliferation and activation, and reduced fibrosis. In diabetic db/db mice, administration of DAPA remarkably ameliorated diabetes-induced STAT3 activation, YY1 nuclear translocation, CF proliferation and activation, and reduced cardiac fibrosis and dysfunction. These in vitro and in vivo effects of DAPA were ameliorated by colivelin TFA, a potent activator of STAT3. Intriguingly, knockdown of SGLT2 did not have an inhibitory effect on CF proliferation and activation in db/db mice. Conclusion: DAPA reduces cardiac fibrosis and DCM. This may, at least in part, be attributable to the repression of the STAT3-YY1 signaling axis-mediated CF proliferation and activation, independent of SGLT2 inhibition. 
کلیدواژه‌های انگلیسی مقاله Dapagliflozin, Diabetic cardiomyopathy, Fibroblast, Signal transducer and - activator of transcription 3 Yin Yang 1
نویسندگان مقاله | Xing-Yi Shen
Department of Cardiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, China


| Zuo Hu
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China


| Zuo Hu
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China


| Hao Xie
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
نشانی اینترنتی https://ijbms.mums.ac.ir/article_26547.html
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