Sirtuin 1 is upregulated in young obese Zucker rat cerebral arteries

摘要

Many diseases, including metabolic syndrome, are characterised by endothelial dysfunction mediated by reduced nitric oxide bioavailability and oxidative stress. Sirtuin 1 is a protein deacetylase that targets endothelial nitric oxide synthase resulting in enhanced nitric oxide bioavailability. Although it has been highlighted as a potential therapeutic target, we still have no understanding of vascular SIRT1 changes during obesity. Therefore, the aim of the present study was to measure vascular function, SIRT1 protein levels of expression and markers of oxidative stress in obese Zucker rats. Middle cerebral arteries from nondiabetic obese and lean Zucker rats were mounted in a pressure myograph to assess nitric oxide-dependent dilations. Western blotting was used to measure protein levels of SIRT1, p53, acetylated p53, eNOS, phosphorylated eNOS and markers of oxidative stress (nitrotyrosine, Nox4 and SOD2) in cerebral vascular tissue. SIRT1 expression was two-fold greater in both cerebral arteries and aorta from obese compared to lean Zucker rats. Acetylation of p53 at the SIRT1-specific lysine 379 site was markedly decreased. At the same time, there was noted cerebral vascular impairment however markers of oxidative stress were not increased. In fact, Nox4 appeared to be downregulated in obesity. Thus, SIRT1 protein levels within the vasculature are greater in obese compared to lean Zucker rats and are associated with higher SIRT1 activity and lower Nox4 expression. We propose that the increased expression and activity of SIRT1 may be a vascular adaptive mechanism in obesity, aiming to prevent oxidative stress.