SRT2104 attenuates diabetes-induced aortic endothelial dysfunction via inhibition of P53

Abstract

Endothelial dysfunction contributes to diabetic macrovascular complications. Sirtuin 1 (SIRT1) protects against diabetic vasculopathy. SRT2104 is a novel SIRT1 activator and was not previously studied for its effects on diabetes-induced aortic endothelial dysfunction. Additionally, whether or to what extent deacetylation of P53, a substrate of SIRT1, is required for the effects of SIRT1 activation was unclear, given the fact that SIRT1 has multiple targets. Moreover, little was known about the pathogenic role of P53 in diabetes-induced aortic injury. To these ends, diabetes was induced by streptozotocin in C57BL/6 mice. The diabetic mice developed enhanced aortic contractility, oxidative stress, inflammation, P53 hyperacetylation and a remarkable decrease in SIRT1 protein, the effects of which were rescued by SRT2104. In HG-treated endothelial cells (ECs), siRNA and SRT2104 produced similar effects on the induction of SIRT1 and the inhibition of P53 acetylation, oxidative stress and inflammation. Interestingly, SRT2104 failed to further enhance these effects in the presence of siRNA. Moreover, P53 activation by nutlin3a completely abolished SRT2104's protection against HG-induced oxidative stress and inflammation. Further, forced activation of P53 by nutlin3a increased aortic contractility in the healthy mice and generated endothelial oxidative stress and inflammation in both the normal glucose-cultured ECs and the aortas of the healthy mice. Collectively, the present study demonstrates that P53 deacetylation predominantly mediates SRT2104's protection against diabetes-induced aortic endothelial dysfunction and highlights the pathogenic role of P53 in aortic endothelial dysfunction.

Inhibition of P53/miR‐34a improves diabetic endothelial dysfunction via activation of SIRT1

“…5,6 P53 is highly expressed in the endothelium/endothelial cells (ECs) under hyperglycaemia/high glucose (HG) conditions. 5,6 P53 is highly expressed in the endothelium/endothelial cells (ECs) under hyperglycaemia/high glucose (HG) conditions.…”

“…5,6 Acetylation of P53 is critical for its stabilization and function. 5,9 This effect enhanced endothelial oxidative stress and inflammation, resulting in endothelial senescence and dysfunction. 5,9 This effect enhanced endothelial oxidative stress and inflammation, resulting in endothelial senescence and dysfunction.…”

“…8 We and others have observed hyperacetylation of P53 in the HG-treated ECs and in the aortas of diabetic mice. 5,9 Notably, deacetylation of P53 by sirtuin 1 (SIRT1) mitigated the HG-induced endothelial oxidative stress and inflammation, 5 and improved endothelial dysfunction. 5,9 Notably, deacetylation of P53 by sirtuin 1 (SIRT1) mitigated the HG-induced endothelial oxidative stress and inflammation, 5 and improved endothelial dysfunction.…”

“…5,9 This effect enhanced endothelial oxidative stress and inflammation, resulting in endothelial senescence and dysfunction. 5,9 On the contrary, forced activation of P53 by nutlin3a increased aortic contractility in healthy mice and generated endothelial oxidative stress and inflammation in both the normal glucose (NG)-cultured ECs and the aortas of the healthy mice, demonstrating that P53 plays a crucial pathogenic role in endothelial dysfunction. 5,9 On the contrary, forced activation of P53 by nutlin3a increased aortic contractility in healthy mice and generated endothelial oxidative stress and inflammation in both the normal glucose (NG)-cultured ECs and the aortas of the healthy mice, demonstrating that P53 plays a crucial pathogenic role in endothelial dysfunction.…”

“…5,9 Notably, deacetylation of P53 by sirtuin 1 (SIRT1) mitigated the HG-induced endothelial oxidative stress and inflammation, 5 and improved endothelial dysfunction. 5 Collectively, these findings provide a rationale for investigating the effect of P53 inhibition on diabetic endothelial dysfunction. 5 Collectively, these findings provide a rationale for investigating the effect of P53 inhibition on diabetic endothelial dysfunction.…”