Sirt5 as a mediator of endothelial and vascular dysfunction: potential therapeutic target in aging-related vascular diseases

Abstract Background Aging is one of the most dominant cardiovascular (CV) risk factors. Sirt5 belongs to the lifespan-regulating sirtuin superfamily as a protein deacylase. However, its regulatory effects on vascular function and aging are yet unclear. Purpose We therefore aimed to investigate the roles of Sirt5 on endothelial and vascular function during aging, decipher the underlying mechanisms, and to explore its potential as a therapeutic target through in vivo and in vitro studies. Methods Aortic expression of Sirt5 were studied in C5BL/6 wild type (WT) mice during aging, followed by vascular functional and structural assessment in WT mice and Sirt5-overexpressing mice (Sirt5/Tg) using the established myograph system and histological staining respectively. Furthermore, the regulatory role of Sirt5 on endothelial function was investigated in senescent primary human aortic endothelial cells (HAECs, passages 13-15) by studying its interference with endothelial nitric oxide synthase (eNOS) expression and activity in knock-down experiments using siRNA. The therapeutic potential of Sirt5 inhibition was explored at the tissue level in myograph experiments. Results Aged WT mice had increased level of Sirt5 in aorta compared to the young ones. Overexpression of Sirt5 in vivo led to significantly reduced aortic endothelial-dependent relaxation and displayed thicker collagen deposition in the adventitia compared to aged WT controls. The reduction of vascular relaxing response in Sirt5/Tg mice was prevented by an addition of eNOS inhibitor (L-name), indicating that Sirt5 regulated vascular function through the eNOS pathway. In senescent HAECs, knock-down of Sirt5 markedly induced total eNOS expression and increased its activity (phospho-eNOS Ser1177), further confirming the regulatory role of Sirt5 on eNOS pathway. In line with the above, aorta from aged WT mice displayed improved endothelial function after pharmacological inhibition of Sirt5. Conclusion Vascular Sirt5 expression increases with age and contributes to aging-related endothelial dysfunction by downregulating the eNOS pathway. Thus, Sirt5 inhibition may represent a novel therapeutic approach to maintain vascular function during aging. Ongoing studies will investigate Sirt5 silencing in-vivo using RNA interference for its therapeutic potential to prevent aging-related vascular dysfunction.