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Empagliflozin activates JAK2/STAT3 signaling and protects cardiomyocytes from hypoxia/reoxygenation injury under high glucose conditions

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Abstract

The morbidity and mortality rates of cardiovascular disease are markedly higher in patients with diabetes than in non-diabetic patients, including patients with ischemia–reperfusion injury (IRI). However, the cardiovascular protective effects of Empagliflozin (EMPA) on IRI in diabetes mellitus have rarely been studied. In this study, we established a cardiomyocyte hypoxia/reoxygenation (H/R) injury model to mimic myocardial I/R injuries that occur in vivo. H9C2 cells were subjected to high glucose (HG) treatment plus H/R injury to mimic myocardial I/R injuries that occur in diabetes mellitus. Next, different concentrations of EMPA were added to the H9C2 cells and its protective effect was detected. STAT3 knockdown with recombinant plasmids was used to determine its roles. Our results showed that H/R injury-induced cell apoptosis, necroptosis, oxidative stress, and endoplasmic reticulum stress were further promoted by HG conditions, and HG treatment plus an H/R injury inhibited the activation of JAK2/STAT3 signaling. EMPA was found to protect against H/R-induced cardiomyocyte injury under HG conditions and activate JAK2/STAT3 signaling, while down-regulation of STAT3 reversed the protective effect of EMPA. When taken together, these findings indicate that EMPA protects against I/R-induced cardiomyocyte injury by activating JAK2/STAT3 signaling under HG conditions. Our results clarified the mechanisms that underlie the cardiovascular protective effects of EMPA in diabetes mellitus and provide new therapeutic targets for IRI in diabetes mellitus.

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Acknowledgements

This research is supported by Scientific Research Fund of the Third Affiliated Hospital of Southern University of Science and Technology (No. 2020-D1).

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Authors and Affiliations

  1. Department of Cardiology, South University of Science and Technology Hospital, 6019 Liuxian Avenue, Xili, Nanshan District, Shenzhen, 518000, Guangdong, People’s Republic of China

    Fan Zhang, Xudong Cao, Chunhui Zhao, Li Chen & Xiaolin Chen

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  1. Fan Zhang
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  2. Xudong Cao
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  3. Chunhui Zhao
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  4. Li Chen
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  5. Xiaolin Chen
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FZ and XC designed the research. FZ and XC collected the data. CZ and LC analyzed the data. FZ and XC wrote or revised the manuscript.

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Correspondence to Xiaolin Chen.

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Zhang, F., Cao, X., Zhao, C. et al. Empagliflozin activates JAK2/STAT3 signaling and protects cardiomyocytes from hypoxia/reoxygenation injury under high glucose conditions. J Thromb Thrombolysis 55, 116–125 (2023). https://doi.org/10.1007/s11239-022-02719-0

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