title: The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice.
abstract: Reductions in arterial SIRT1 expression and activity with aging are linked to vascular endothelial dysfunction. We tested the hypothesis that the specific SIRT1 activator SRT1720 improves endothelial function [endothelium-dependent dilation (EDD)] in old mice. Young (4-9 mo) and old (29-32 mo) male B6D2F1 mice treated with SRT1720 (100 mg/kg body wt) or vehicle for 4 wk were studied with a group of young controls. Compared with the young controls, aortic SIRT1 expression and activity were reduced (P < 0.05) and EDD was impaired (83 ± 2 vs. 96 ± 1%; P < 0.01) in old vehicle-treated animals. SRT1720 normalized SIRT1 expression/activity in old mice and restored EDD (95 ± 1%) by enhancing cyclooxygenase (COX)-2-mediated dilation and protein expression in the absence of changes in nitric oxide bioavailability. Aortic superoxide production and expression of NADPH oxidase 4 (NOX4) were increased in old vehicle mice (P < 0.05), and ex vivo administration of the superoxide scavenger TEMPOL restored EDD in that group. SRT1720 normalized aortic superoxide production in old mice, without altering NOX4 and abolished the improvement in EDD with TEMPOL, while selectively increasing aortic antioxidant enzymes. Aortic nuclear factor-κB (NF-κB) activity and tumor necrosis factor-α (TNF-α) were increased in old vehicle mice (P < 0.05), whereas SRT1720 normalized NF-κB activation and reduced TNF-α in old animals. SIRT1 activation with SRT1720 ameliorates vascular endothelial dysfunction with aging in mice by enhancing COX-2 signaling and reducing oxidative stress and inflammation. Specific activation of SIRT1 is a promising therapeutic strategy for age-related endothelial dysfunction in humans.
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado; lindsey.gano@ucdenver.edu.
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: Gano
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado; Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah; and Geriatrics Research Education and Clinical Center, Veteran's Affairs Medical Center, Salt Lake City, Utah.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Donato
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Hamza M
authors.initials: HM
authors.lastname: Pasha
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hearon
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Amy L
authors.initials: AL
authors.lastname: Sindler
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Seals
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013113:Spin Labels; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D006576:Heterocyclic Compounds, 4 or More Rings; D016328:NF-kappa B; C525422:SRT1720; D013113:Spin Labels; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C001803:tempol
keywords: COX-2 dilation; SIRT1; aging; superoxide; vascular inflammation