Metformin modulates hyperglycemia‐induced endothelial dysfunction through SIRT1

Endothelial dysfunction, detected at an early stage in the development of diabetes‐related microvascular disease, is associated with accelerated endothelial senescence. Hyperglycemia‐induced endothelial senescence is an important contributing factor that promotes the development of ageing‐associated cardiovascular events. Clinical data indicate that the hypoglycemic agent, metformin, has an endothelial protective action. Our data with mouse microvascular endothelial cells cultured in high glucose (HG, 40mM), versus normal glucose (NG, 11mM), indicate a significant reduction in SIRT1 protein, an increase in FoxO‐1 and p53 acetylation along with an increase in the p21 levels and senescence‐associated beta‐galactosidase activity. Metformin treatment significantly abolishes the reduction of SIRT1 level and modulates the SIRT1 downstream targets FoxO‐1, p53/p21. We also investigated the role of small noncoding RNAs, miRNAs, as molecular targets that regulate SIRT1 expression. Our data demonstrates that hyperglycemia‐induced downregulation of SIRT1 plays a crucial role in diabetes‐induced endothelial senescence and, furthermore, the endothelial protective effect of metformin against HG‐induced endothelial dysfunction is, at least in part, due to its effects on SIRT1 expression and/or activity.This project was funded by grant # NPRP 4–910‐3–244 & NPRP 08–165‐3–054