Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation

Ying Zhou; Shi Tai; Ningjie Zhang; Liyao Fu; Yongjun Wang

doi:10.1016/j.biopha.2023.115213

Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation

Biomed Pharmacother. 2023 Sep:165:115213. doi: 10.1016/j.biopha.2023.115213. Epub 2023 Jul 28.

Authors

Ying Zhou¹, Shi Tai², Ningjie Zhang³, Liyao Fu⁴, Yongjun Wang⁵

Affiliations

¹ Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha 410011, China; Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, China.
² Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, China.
³ Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha 410011, China.
⁴ Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha 410011, China; Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410000, China. Electronic address: fuliyao2017@csu.edu.cn.
⁵ Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha 410011, China. Electronic address: wangyongjun@csu.edu.cn.

PMID: 37517289
DOI: 10.1016/j.biopha.2023.115213

Abstract

Recent studies have demonstrated that dapagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, prevents endothelial dysfunction; however, direct effects of dapagliflozin on the endothelium under oxidative stress and the underlying mechanism of action are not completely understood. This study aimed to define the role and related mechanisms of dapagliflozin in hydrogen peroxide (H₂O₂)-induced endothelial dysfunction. The endothelium-dependent vasorelaxation effect of dapagliflozin was assessed in an organ bath study. Endothelial dysfunction was assessed using protein expression level and phosphorylation of endothelial nitric oxide synthase (eNOS), nitric oxide (NO), reactive oxygen species (ROS), senescence-associated beta-galactosidase (SA-β-gal) activity, and senescence marker proteins (p21, p53). Co-immunoprecipitation and protein acetylation were performed to detect protein interactions. Dapagliflozin exerted a direct vasorelaxant effect in the aortic rings of C57BL/6 J mice. Furthermore, there was a significant improvement in endothelium-dependent vasorelaxation in dapagliflozin-treated diabetic mice compared to vehicle controls. Moreover, intracellular ROS levels and ONOO- levels, increased by H₂O₂, were reduced by dapagliflozin. Importantly, dapagliflozin inhibited H₂O₂-induced senescence in the human umbilical vein endothelial cells (HUVECs), as indicated by reduced SA-β-gal, p21, and p53. Mechanistically, dapagliflozin reversed the H₂O₂-mediated inhibition of eNOS serine phosphorylation and sirtuin 1 (SIRT1) expression in endothelial cells. In particular, SIRT1-mediated eNOS deacetylation is reportedly involved in dapagliflozin-enhanced eNOS activity. These findings indicate that dapagliflozin ameliorates endothelial dysfunction by restoring eNOS activity, restoring NO bioavailability, and reducing ROS generation via SIRT1 activation in oxidative stress-stimulated endothelial cells.

Keywords: Dapagliflozin; Endothelial cells; Oxidative stress; SIRT1; Senescence, SGLT2.

MeSH terms

Animals
Cells, Cultured
Cellular Senescence
Diabetes Mellitus, Experimental* / metabolism
Human Umbilical Vein Endothelial Cells
Humans
Hydrogen Peroxide / pharmacology
Mice
Mice, Inbred C57BL
Nitric Oxide Synthase Type III / metabolism
Oxidative Stress
Reactive Oxygen Species / metabolism
Sirtuin 1* / metabolism
Tumor Suppressor Protein p53 / metabolism

Substances

Sirtuin 1
dapagliflozin
Reactive Oxygen Species
Hydrogen Peroxide
Tumor Suppressor Protein p53
Nitric Oxide Synthase Type III