Dapagliflozin protects against doxorubicin-induced cardiotoxicity by restoring STAT3

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Title:	Dapagliflozin protects against doxorubicin-induced cardiotoxicity by restoring STAT3
Authors:	Chang, Wei-Ting Shih, Jhih-Yuan Lin, Yu-Wen Chen, Zhih-Cherng Kan, Wei-Chih Lin, Tsung-Hsien Hong, Chon-Seng
Contributors:	National Cheng Kung University Chi Mei Hospital Southern Taiwan University of Science & Technology Department of Health and Nutrition, Chia Nan University of Pharmacy & Science Chi Mei Hospital Chung Hua University Kaohsiung Medical University Kaohsiung Medical University Kaohsiung Medical University Hospital
Keywords:	h9c2 cells inhibition stress
Date:	2022
Issue Date:	2023-12-11 13:56:39 (UTC+8)
Publisher:	SPRINGER HEIDELBERG
Abstract:	Doxorubicin (Dox), an effective therapy in different types of cancer, is known to exhibit cardiotoxic effects. Despite previous studies indicating the benefits of dapagliflozin (DAPA) in patients experiencing heart failure, it remains uncertain whether DAPA exerts a protective effect on Dox-induced cardiac dysfunction. Signal transducer and activator of transcription 3 (STAT3) participates in various mechanisms of cardioprotection. Herein, we aimed to investigate the effects of DAPA on Dox-induced cardiotoxicity and the role of STAT3. Sprague-Dawley rats were pretreated with oral DAPA for 6 weeks followed by Dox for 4 weeks. Sequential echocardiography was applied to assess cardiac function. For in vitro analysis, cardiomyocytes were treated with 10 mu M DAPA and subsequently exposed to 1 mu M Dox. The expression of reactive oxygen species- and apoptosis-related proteins was measured. Using STAT3 siRNA, we further examined the effects of STAT3 effect on DAPA-associated protection against Dox-induced apoptosis. In rats treated with Dox, DAPA significantly reduced cardiac fibrosis and improved cardiac function and hemodynamics. Additionally, DAPA effectively inhibited Dox-induced apoptosis and reactive oxygen species (ROS) in cardiomyocytes. Mechanistically, we showed that DAPA decreased cardiac expression of Bax and cleaved caspase 3 but increased Bcl-2 expression. DAPA also significantly rescued Dox-suppressed STAT3 expression. Conversely, knocking down STAT3 in cardiomyocytes reversed the DAPA-related protective effects on Dox-induced cell apoptosis and ROS. Collectively, our findings indicate that DAPA could be useful for preventing Dox-induced cardiotoxicity by restoring STAT3.
Relation:	Archives of Toxicology, v.96, n.7, pp.2021-2032
Appears in Collections:	[Dept. of Health and Nutrition (including master's program)] Periodical Articles

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