Hence, the present study has uncovered a P53/miR-34a/SIRT1 pathway that leads to endothelial dysfunction, suggesting that P53/miR-34a inhibition could be a viable strategy in the management of diabetic macrovascular diseases.
Furthermore, a lower expression of Sirt1 was correlated with glucose metabolic abnormalities, aortic endothelial dysfunction and endothelial apoptosis as evidenced by western blot analysis and ELISA in mice.
Furthermore, we observed that miR-34a-mediated endothelial dysfunction is associated with decreased miR-34a direct-target protein, sirtuin-1, and increased p53 expression in whole lungs and ECs.
Furthermore, examination of the overexpression of forkhead box O1 (FOXO1), a transcription factor substrate of SIRT1, in HUVECs and db/db mice revealed that RES activated SIRT1 to restore hyperglycemia-triggered endothelial dysfunction and disturbance of angiogenesis, followed by the promotion of diabetic wound healing in a c-Myc-dependent manner.
We compared wild-type and fibrosis-prone endothelial sirtuin 1-deficient (Sirt1<sup>endo-/-</sup>) mice, the latter being a model of global endothelial dysfunction.
This spectrum of abnormalities associated with SIRT1 deficiency in endothelial cells is essential for understanding the origins and features of endothelial dysfunction in a host of cardiovascular and renal diseases.
The events that possibly overlay include OS-induced sequestration of SIRT1 to caveolae facilitating cav1-SIRT1 association; potential increase in lysine acetylation of enzymes such as eNOS and PRMT1 leading to enhanced ADMA formation; imbalance in acetylation-methylation ratio (AMR); diminished NO generation and ED.
A large body of evidence has showed that SIRT1 induces both cellular and systemic protective effects in the cardiovascular system by preventing stress-induced apoptosis and senescence, and mitigating endothelial dysfunction.
Recently, we demonstrated that SIRT1 protects blood vessels from hyperglycemia-induced endothelial dysfunction through a novel mechanism involving the downregulation of p66Shc expression.
In this study, we investigated the role of SIRT1, a class III histone deacetylase, in the regulation of p66Shc expression and hyperglycemia-induced endothelial dysfunction.