Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation
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. Thi...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223010041 |
| _version_ | 1797744059336359936 |
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| author | Ying Zhou Shi Tai Ningjie Zhang Liyao Fu Yongjun Wang |
| author_facet | Ying Zhou Shi Tai Ningjie Zhang Liyao Fu Yongjun Wang |
| author_sort | Ying Zhou |
| collection | DOAJ |
| description | 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. |
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| format | Article |
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| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-12T15:04:18Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
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| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-55a52079909442bf804481d4c7a727062023-08-13T04:53:03ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-09-01165115213Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activationYing Zhou0Shi Tai1Ningjie Zhang2Liyao Fu3Yongjun Wang4Department 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, ChinaDepartment of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, ChinaDepartment of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha 410011, ChinaDepartment 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; Correspondence to: Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, No. 139, Middle Renmin Road, Changsha, 410011 Hunan, China.Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha 410011, China; Correspondence to: Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, No. 139, Middle Renmin Road, Changsha, 410011 Hunan, China.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.http://www.sciencedirect.com/science/article/pii/S0753332223010041DapagliflozinEndothelial cellsOxidative stressSIRT1Senescence, SGLT2 |
| spellingShingle | Ying Zhou Shi Tai Ningjie Zhang Liyao Fu Yongjun Wang Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation Biomedicine & Pharmacotherapy Dapagliflozin Endothelial cells Oxidative stress SIRT1 Senescence, SGLT2 |
| title | Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation |
| title_full | Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation |
| title_fullStr | Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation |
| title_full_unstemmed | Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation |
| title_short | Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation |
| title_sort | dapagliflozin prevents oxidative stress induced endothelial dysfunction via sirtuin 1 activation |
| topic | Dapagliflozin Endothelial cells Oxidative stress SIRT1 Senescence, SGLT2 |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223010041 |
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