期刊
BIOCHEMICAL PHARMACOLOGY
卷 85, 期 9, 页码 1288-1296出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.02.015
关键词
SIRT1; Endothelial dysfunction; NADPH oxidase; PPAR alpha
资金
- Comision Interministerial de Ciencia y Tecnologia [SAF2011-28150, SAF2010-22066-C02-01, SAF2010-22066-C02-02]
- Ministerio de Economia y Competitividad, Instituto de Salud Carlos III, Spain [Red HERACLES RD06/0009]
- Spanish Ministry of Science and Education
- Ministerio de Ciencia e Innovacion Campus de Excelencia Internacional (Programa GREIB), Spain
Vascular aging is characterized by up-regulation of NADPH oxidase, oxidative stress and endothelial dysfunction. Previous studies demonstrate that the activity of the evolutionarily conserved NAD(+)-dependent deacetylase SIRT1 declines with age and that pharmacological activators of SIRT1 confer significant anti-aging cardiovascular effects. To determine whether dysregulation of SIRT1 promotes NADPH oxidase-dependent production of reactive oxygen species (ROS) and impairs endothelial function we assessed the effects of three structurally different inhibitors of SIRT1 (nicotinamide, sirtinol, EX527) in aorta segments isolated from young Wistar rats. Inhibition of SIRT1 induced endothelial dysfunction, as shown by the significantly reduced relaxation to the endothelium-dependent vasodilators acetylcholine and the calcium ionophore A23187. Endothelial dysfunction induced by SIRT1 inhibition was prevented by treatment of the vessels with the NADPH oxidase inhibitor apocynin or superoxide dismutase. Inhibition of SIRT1 significantly increased vascular superoxide production, enhanced NADPH oxidase activity, and mRNA expression of its subunits p22(phox) and NOX4, which were prevented by resveratrol. Peroxisome proliferator-activated receptor-alpha (PPAR alpha) activation mimicked the effects of resveratrol while PPAR alpha inhibition prevented the effects of this SIRT1 activator. SIRT1 co-precipitated with PPAR alpha and nicotinamide increased the acetylation of the PPAR alpha coactivator PGC-1 alpha, which was suppressed by resveratrol. In conclusion, impaired activity of SIRT1 induces endothelial dysfunction and up-regulates NADPH oxidase-derived ROS production in the vascular wall, mimicking the vascular aging phenotype. Moreover, a new mechanism for controlling endothelial function after SIRT1 activation involves a decreased PGC-1 alpha acetylation and the subsequent PPAR alpha activation, resulting in both decreased NADPH oxidase-driven ROS production and NO inactivation. (C) 2013 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据