title: SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: implications for vascular aging.
abstract: 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-α (PPARα) activation mimicked the effects of resveratrol while PPARα inhibition prevented the effects of this SIRT1 activator. SIRT1 co-precipitated with PPARα and nicotinamide increased the acetylation of the PPARα coactivator PGC-1α, 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-1α acetylation and the subsequent PPARα activation, resulting in both decreased NADPH oxidase-driven ROS production and NO inactivation.
authors: Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.
authors: María José
authors: MJ
authors: Zarzuelo
authors: Rocío
authors: R
authors: López-Sepúlveda
authors: Manuel
authors: M
authors: Sánchez
authors: Miguel
authors: M
authors: Romero
authors: Manuel
authors: M
authors: Gómez-Guzmán
authors: Zoltan
authors: Z
authors: Ungvary
authors: Francisco
authors: F
authors: Pérez-Vizcaíno
authors: Rosario
authors: R
authors: Jiménez
authors: Juan
authors: J
authors: Duarte
mesh_terms: D000107:Acetylation; D000375:Aging / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D022461:Caveolins / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D066298:In Vitro Techniques; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D022461:Caveolins; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D013267:Stilbenes; D014157:Transcription Factors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D006152:Cyclic GMP; D000077185:Resveratrol