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

Abstract
Endothelial dysfunction plays a significant role in diabetic macrovascular complications, with Sirtuin 1 (SIRT1) offering protective effects against diabetic vasculopathy. SRT2104 is a novel activator of SIRT1 that had not been previously studied for its potential to address diabetes-induced aortic endothelial dysfunction. It was also unclear whether the deacetylation of P53, a known SIRT1 substrate, was crucial to the therapeutic effects of SIRT1 activation, given SIRT1’s broad range of targets. Additionally, the pathogenic role of P53 in diabetes-induced aortic injury remained poorly understood. In this study, diabetes was induced in C57BL/6 mice using streptozotocin. The diabetic mice exhibited increased aortic contractility, oxidative stress, inflammation, P53 hyperacetylation, and a significant reduction in SIRT1 protein, all of which were reversed by SRT2104 treatment. In high-glucose (HG)-treated endothelial cells (ECs), both P53 siRNA and SRT2104 similarly increased SIRT1 expression and reduced P53 acetylation, oxidative stress, and inflammation. Notably, SRT2104 did not further enhance these effects when P53 was silenced with siRNA. Moreover, activation of P53 using nutlin3a completely negated the protective effects of SRT2104 against HG-induced oxidative stress and inflammation. Additionally, forced P53 activation via nutlin3a increased aortic contractility in healthy mice and induced endothelial oxidative stress and inflammation in both normal glucose-cultured ECs and aortas from healthy mice. In summary, this study demonstrates that P53 deacetylation plays a central role in mediating the protective effects of SRT2104 against diabetes-induced aortic endothelial dysfunction and underscores the pathogenic contribution of P53 in this process.