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  2. Dapagliflozin attenuates pressure overload-induced myocardial remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress

Dapagliflozin attenuates pressure overload-induced myocardial remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress

  • Acta Pharmacol Sin. 2022 Jul;43(7):1721-1732. doi: 10.1038/s41401-021-00805-2.
Fang-Fang Ren 1 Zuo-Yi Xie 1 Yi-Na Jiang 1 Xuan Guan 1 Qiao-Ying Chen 1 Teng-Fang Lai 2 Lei Li 3
Affiliations

Affiliations

  • 1 Department of Cardiology, Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
  • 2 Department of Cardiology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, China. ltf15907861037@163.com.
  • 3 Department of Cardiology, Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China. lileiii@hotmail.com.
Abstract

Endoplasmic reticulum stress-mediated Apoptosis plays a vital role in the occurrence and development of heart failure. Dapagliflozin (DAPA), a new type of sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an oral hypoglycemic drug that reduces glucose reabsorption by the kidneys and increases glucose excretion in the urine. Studies have shown that DAPA may have the potential to treat heart failure in addition to controlling blood sugar. This study explored the effect of DAPA on endoplasmic reticulum stress-related Apoptosis caused by heart failure. In vitro, we found that DAPA inhibited the expression of cleaved Caspase 3, Bax, C/EBP homologous protein (CHOP), and glucose-regulated protein78 (GRP78) and upregulated the cardiomyoprotective protein Bcl-2 in angiotensin II (Ang II)-treated cardiomyocytes. In addition, DAPA promoted the expression of silent information regulator factor 2-related Enzyme 1 (SIRT1) and suppressed the expression of activating transcription factor 4 (ATF4) and the ratios p-PERK/PERK and p-eIF2α/eIF2α. Notably, the therapeutic effect of DAPA was weakened by pretreatment with the SIRT1 Inhibitor EX527 (10 μM). Simultaneous administration of DAPA inhibited the Ang II-induced transformation of fibroblasts into myofibroblasts and inhibited fibroblast migration. In summary, our present findings first indicate that DAPA could inhibit the PERK-eIF2α-CHOP axis of the ER stress response through the activation of SIRT1 in Ang II-treated cardiomyocytes and ameliorate heart failure development in vivo.

Keywords

DAPA; SIRT1; endoplasmic reticulum stress; heart failure; ventricular remodeling.

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