Angiotensin II‐induced redox‐sensitive SGLT1 and 2 expression promotes high glucose‐induced endothelial cell senescence

• Published in: Journal of cellular and molecular medicine Vol. 24; no. 3; pp. 2109 - 2122
• Main Authors: Khemais‐Benkhiat, Sonia, Belcastro, Eugenia, Idris‐Khodja, Noureddine, Park, Sin‐Hee, Amoura, Lamia, Abbas, Malak, Auger, Cyril, Kessler, Laurence, Mayoux, Eric, Toti, Florence, Schini‐Kerth, Valérie B.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2020; Wiley Open Access; John Wiley and Sons Inc
• Subjects: Aging; Aging - drug effects; Aging - metabolism; Angiotensin; Angiotensin II; Angiotensin II - pharmacology; angiotensin system; Animals; Antidiabetics; Benzhydryl Compounds - pharmacology; Cardiovascular diseases; Cells, Cultured; Cellular Senescence - drug effects; Coronary artery; Coronary vessels; Diabetes; Diabetes mellitus; Down-Regulation - drug effects; Endothelial cells; Endothelial Cells - drug effects; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Flow cytometry; Gene expression; Glucose - metabolism; Glucosides - pharmacology; high glucose; Hydrogen peroxide; Immunofluorescence; Life Sciences; mRNA; Nitric oxide; Nitric Oxide Synthase Type III - metabolism; Original; Oxidation-Reduction - drug effects; Oxidative stress; Oxidative Stress - drug effects; Penicillin; Pharmaceutical sciences; Pharmacology; Proteins; pro‐atherothrombotic markers; Senescence; SGLT2; Sodium-Glucose Transporter 1 - metabolism; Sodium-Glucose Transporter 2 - metabolism; Swine; Tissue factor; Veins & arteries; β-Galactosidase; France; senescence; endothelial cells; pro-atherothrombotic markers; high glucose; SGLT2; angiotensin system
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.14233

High glucose (HG)‐induced endothelial senescence and dysfunction contribute to the increased cardiovascular risk in diabetes. Empagliflozin, a selective sodium glucose co‐transporter2 (SGLT2) inhibitor, reduced the risk of cardiovascular mortality in type 2 diabetic patients but the protective mechanism remains unclear. This study examines the role of SGLT2 in HG‐induced endothelial senescence and dysfunction. Porcine coronary artery cultured endothelial cells (ECs) or segments were exposed to HG (25 mmol/L) before determination of senescence‐associated beta‐galactosidase activity, protein level by Western blot and immunofluorescence staining, mRNA by RT‐PCR, nitric oxide (NO) by electron paramagnetic resonance, oxidative stress using dihydroethidium and glucose uptake using 2‐NBD‐glucose. HG increased ECs senescence markers and oxidative stress, down‐regulated eNOS expression and NO formation, and induced the expression of VCAM‐1, tissue factor, and the local angiotensin system, all these effects were prevented by empagliflozin. Empagliflozin and LX‐4211 (dual SGLT1/2 inhibitor) reduced glucose uptake stimulated by HG and H2O2 in ECs. HG increased SGLT1 and 2 protein levels in cultured ECs and native endothelium. Inhibition of the angiotensin system prevented HG‐induced ECs senescence and SGLT1 and 2 expression. Thus, HG‐induced ECs ageing is driven by the local angiotensin system via the redox‐sensitive up‐regulation of SGLT1 and 2, and, in turn, enhanced glucotoxicity.