Vascular senescence reflects the limited ability of vascular cells to divide and proliferate and is accompanied by specific phenotypic changes in morphology, gene expression and function. In endothelial cells, these changes result in a phenotype that is pro-inflammatory, pro-atherosclerotic, and prothrombotic. Hyperglycemia-mediated oxidative stress elicits irreversible growth arrest in endothelial cells, which is referred as “stress-induced premature senescence”. Endothelial cell senescence has recently been postulated as an important cause of type-2 diabetes-associated vascular aging. High glucose-induced endothelial senescence exaggerates vascular inflammation and thrombosis in the vessels, promoting the development of diabetic-associated cardiovascular events. Sirtuin 1 (SIRT1) is highly expressed in vasculature and distinctively controls angiogenic signaling in endothelial cells. Recently, SIRT1 has been identified as an important regulator of endothelial cell senescence-like growth arrest and dysfunction. However, the mechanism underlying the high glucose induced endothelial cell senescence leading to vascular dysfunction is not fully understood.

Mouse microvessel endothelial cells were exposed to normal (11mM) and high glucose (40mM) for 72 hrs. The level of SIRT1, p21 and phospho-acetylated status of Foxo1 were measured by immunoblotting. To measure senescence, cells were fixed and stained for senescence-associated B-galactosidase activity. The percentage of B-galactosidase positively stained (blue color) cells was counted.

Immunoblot analysis reveals that high glucose exposure caused a significant reduction of SIRT1 level along with altered phospho-acetylation levels of Foxo1 proteins. Furthermore, high glucose treatment increased the percentage of senescence-associated B-galactosidase activity in endothelial cells.

Collectively, these data suggest that high glucose induced depletion of SIRT1 plays a crucial role in diabetes-associated endothelial cell senescence and strengthens concept that activation of SIRT1 is an important target for pharmaco-therapy for diabetes-associated endothelial dysfunction and vascular aging. This abstract is part of project funded by: NPRP: 08-165-3-054


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