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. Epub 2021 Dec 1.

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.

MeSH terms

  • Animals
  • Apoptosis
  • Benzhydryl Compounds
  • Endoplasmic Reticulum Stress*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Glucose / pharmacology
  • Glucosides
  • Heart Failure* / drug therapy
  • Mice
  • Sirtuin 1 / metabolism

Substances

  • Benzhydryl Compounds
  • Eukaryotic Initiation Factor-2
  • Glucosides
  • dapagliflozin
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Glucose