Dapagliflozin impedes endothelial cell senescence by activating the SIRT1 signaling pathway in type 2 diabetes

Shi Tai; Ying Zhou; Liyao Fu; Huiqing Ding; Yuying Zhou; Zhiyi Yin; Rukai Yang; Zhenjiang Liu; Shenghua Zhou

doi:10.1016/j.heliyon.2023.e19152

Dapagliflozin impedes endothelial cell senescence by activating the SIRT1 signaling pathway in type 2 diabetes

Heliyon. 2023 Aug 21;9(8):e19152. doi: 10.1016/j.heliyon.2023.e19152. eCollection 2023 Aug.

Authors

Shi Tai¹, Ying Zhou², Liyao Fu², Huiqing Ding¹, Yuying Zhou³, Zhiyi Yin², Rukai Yang¹, Zhenjiang Liu¹, Shenghua Zhou¹

Affiliations

¹ Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China.
² Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha, China.
³ Department of Cardiology, Xiangtan Central Hospital, Xiangtan, 411100, China.

Abstract

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) clinically reduce atherosclerosis and lower blood pressure. However, their impact on endothelial dysfunction in type 2 diabetes (T2D) remains unclear. In this study, we investigated the protective effect and underlying mechanism of the SGLT2 inhibitor dapagliflozin in diabetes.

Methods: Vascular reactivity was measured to assess the vasoprotective effect of dapagliflozin in a mouse model of high glucose (HG)-induced T2D. Pulse wave velocity was measured to quantify arterial stiffness. Protein expression was assessed by western blotting and immunofluorescence, oxidative stress was evaluated using dihydroethidium, nitric oxide was evaluated using the Griess reaction, and cellular senescence was assessed based on senescence-associated beta-galactosidase (SA-β-gal) activity and the expression of senescence markers. Furthermore, the endothelial nitric oxide synthase (eNOS) acetylation status was determined and eNOS interactions with SIRT1 were evaluated by coimmunoprecipitation assays.

Results: Dapagliflozin protected against impaired endothelium-dependent vasorelaxation and improved arterial stiffness in the mouse model of T2D; mouse aortas had significantly reduced levels of senescence activity and senescence-associated inflammatory factors. HG-induced increases in senescence activity, protein marker levels, and oxidative stress in vitro were all ameliorated by dapagliflozin. The decreases in eNOS phosphorylation and nitric oxide (NO) production in senescent endothelial cells were restored by dapagliflozin. SIRT1 expression was reduced in HG-induced senescent endothelial cells, and dapagliflozin restored SIRT1 expression. SIRT1 inhibition diminished the antisenescence effects of dapagliflozin. Coimmunoprecipitation showed that SIRT1 was physically associated with eNOS, suggesting that the effects of dapagliflozin are dependent on SIRT1 activation.

Conclusion: These findings indicate that dapagliflozin protects against endothelial cell senescence by regulating SIRT1 signaling in diabetic mice.

Keywords: Dapagliflozin; Diabetes; Endothelial cells; SGLT2 inhibitor; SIRT1; Senescence.