title: Vascular Smooth Muscle Sirtuin-1 Protects Against Aortic Dissection During Angiotensin II-Induced Hypertension.
abstract: BACKGROUND
  Sirtuin-1 (SirT1), a nicotinamide adenine dinucleotide(+)-dependent deacetylase, is a key enzyme in the cellular response to metabolic, inflammatory, and oxidative stresses; however, the role of endogenous SirT1 in the vasculature has not been fully elucidated. Our goal was to evaluate the role of vascular smooth muscle SirT1 in the physiological response of the aortic wall to angiotensin II, a potent hypertrophic, oxidant, and inflammatory stimulus.
  
  
  RESULTS
  Mice lacking SirT1 in vascular smooth muscle (ie, smooth muscle SirT1 knockout) had drastically high mortality (70%) caused by aortic dissection after angiotensin II infusion (1 mg/kg per day) but not after an equipotent dose of norepinephrine, despite comparable blood pressure increases. Smooth muscle SirT1 knockout mice did not show any abnormal aortic morphology or blood pressure compared with wild-type littermates. Nonetheless, in response to angiotensin II, aortas from smooth muscle SirT1 knockout mice had severely disorganized elastic lamellae with frequent elastin breaks, increased oxidant production, and aortic stiffness compared with angiotensin II-treated wild-type mice. Matrix metalloproteinase expression and activity were increased in the aortas of angiotensin II-treated smooth muscle SirT1 knockout mice and were prevented in mice overexpressing SirT1 in vascular smooth muscle or with use of the oxidant scavenger tempol.
  
  
  CONCLUSIONS
  Endogenous SirT1 in aortic smooth muscle is required to maintain the structural integrity of the aortic wall in response to oxidant and inflammatory stimuli, at least in part, by suppressing oxidant-induced matrix metalloproteinase activity. SirT1 activators could potentially be a novel therapeutic approach to prevent aortic dissection and rupture in patients at risk, such as those with hypertension or genetic disorders, such as Marfan's syndrome.
authors.affiliation: Vascular Biology Section, Boston University Medical Campus, Boston, MA (J.L.F., Y.S., R.A., M.B., R.A.C., F.S.).
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Fry
authors.affiliation: Vascular Biology Section, Boston University Medical Campus, Boston, MA (J.L.F., Y.S., R.A., M.B., R.A.C., F.S.).
authors.forename: Yasunaga
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA (R.T., Y.Z.G., Y.Z.) Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA (R.T.).
authors.forename: Raphaël
authors.initials: R
authors.lastname: Turcotte
authors.affiliation: Department of Mechanical Engineering, Boston University, Boston, MA (X.Y., Y.Z.).
authors.forename: Xunjie
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA (R.T., Y.Z.G., Y.Z.) Health Science Department, Boston University, Boston, MA (Y.Z.G., K.G.M.).
authors.forename: Yuan Z
authors.initials: YZ
authors.lastname: Gao
authors.affiliation: Vascular Biology Section, Boston University Medical Campus, Boston, MA (J.L.F., Y.S., R.A., M.B., R.A.C., F.S.).
authors.forename: Rachid
authors.initials: R
authors.lastname: Akiki
authors.affiliation: Vascular Biology Section, Boston University Medical Campus, Boston, MA (J.L.F., Y.S., R.A., M.B., R.A.C., F.S.).
authors.forename: Markus
authors.initials: M
authors.lastname: Bachschmid
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA (R.T., Y.Z.G., Y.Z.) Department of Mechanical Engineering, Boston University, Boston, MA (X.Y., Y.Z.).
authors.forename: Yanhang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Health Science Department, Boston University, Boston, MA (Y.Z.G., K.G.M.).
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Morgan
authors.affiliation: Vascular Biology Section, Boston University Medical Campus, Boston, MA (J.L.F., Y.S., R.A., M.B., R.A.C., F.S.).
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cohen
authors.affiliation: Vascular Biology Section, Boston University Medical Campus, Boston, MA (J.L.F., Y.S., R.A., M.B., R.A.C., F.S.).
authors.forename: Francesca
authors.initials: F
authors.lastname: Seta
mesh_terms: D000784:Aortic Dissection / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000804:Angiotensin II; D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000473:pathology; D001014:Aortic Aneurysm / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D004547:Elastic Tissue / Q000378:metabolism / Q000473:pathology; D004549:Elastin / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013113:Spin Labels; D013997:Time Factors
chemical_list: D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D013113:Spin Labels; D000804:Angiotensin II; D004549:Elastin; D020782:Matrix Metalloproteinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C001803:tempol
keywords: angiotensin II; aortic dissection; sirtuin‐1; vascular smooth muscle