Dapagliflozin improves endothelial cell dysfunction by regulating mitochondrial production via the SIRT1/PGC-1α pathway in obese mice

Biochem Biophys Res Commun. 2022 Jul 30;615:123-130. doi: 10.1016/j.bbrc.2022.05.022. Epub 2022 May 10.

Abstract

Obesity is closely related to the occurrence of cardiovascular diseases, and an important reason for this is the induction of endothelial cell dysfunction. Mitochondria play an important role in maintaining the function of endothelial cells. In the present study, we examined the effects of the sodium-dependent glucose transporters 2 inhibitor dapagliflozin (DAPA) on the vascular endothelium in obese mice in vivo and on the structure and function of human umbilical vein endothelial cells (HUVECs) in vitro. The results revealed that DAPA rescued vascular endothelial damage in obese mice. Moreover, DAPA reversed the effects of palmitic acid (PA) on the reduction in angiogenesis and the increase in apoptosis in HUVECs. Furthermore, DAPA rescued the reduced mitochondrial membrane potential, mitochondrial viability, energy metabolism, mitochondrial biogenesis and the mitochondrial structural injury caused by PA. DAPA also activated the SIRT1/PGC-1α signaling pathway, while the SIRT1 inhibitor EX-527 abrogated the effects of DAPA on the mitochondria of HUVECs. In summary, our study suggests that DAPA improves endothelial cell mitochondrial function in obese mice by activating the SIRT1/PGC-1α pathway.

Keywords: Dapagliflozin; Endothelial cell; Mitochondria; SIRT1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds
  • Glucosides
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Mice
  • Mice, Obese
  • Mitochondria* / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Sirtuin 1* / metabolism

Substances

  • Benzhydryl Compounds
  • Glucosides
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • dapagliflozin
  • Sirt1 protein, mouse
  • Sirtuin 1