title: Age-Associated Sirtuin 1 Reduction in Vascular Smooth Muscle Links Vascular Senescence and Inflammation to Abdominal Aortic Aneurysm.
abstract: BACKGROUND
  Uncontrolled growth of abdominal aortic aneurysms (AAAs) is a life-threatening vascular disease without an effective pharmaceutical treatment. AAA incidence dramatically increases with advancing age in men. However, the molecular mechanisms by which aging predisposes individuals to AAAs remain unknown.
  
  
  OBJECTIVE
  In this study, we investigated the role of SIRT1 (Sirtuin 1), a class III histone deacetylase, in AAA formation and the underlying mechanisms linking vascular senescence and inflammation.
  
  
  RESULTS
  The expression and activity of SIRT1 were significantly decreased in human AAA samples. SIRT1 in vascular smooth muscle cells was remarkably downregulated in the suprarenal aortas of aged mice, in which AAAs induced by angiotensin II infusion were significantly elevated. Moreover, vascular smooth muscle cell-specific knockout of SIRT1 accelerated angiotensin II-induced formation and rupture of AAAs and AAA-related pathological changes, whereas vascular smooth muscle cell-specific overexpression of SIRT1 suppressed angiotensin II-induced AAA formation and progression in Apoe-/-mice. Furthermore, the inhibitory effect of SIRT1 on AAA formation was also proved in a calcium chloride (CaCl2)-induced AAA model. Mechanistically, the reduction of SIRT1 was shown to increase vascular cell senescence and upregulate p21 expression, as well as enhance vascular inflammation. Notably, inhibition of p21-dependent vascular cell senescence by SIRT1 blocked angiotensin II-induced nuclear factor-κB binding on the promoter of monocyte chemoattractant protein-1 and inhibited its expression.
  
  
  CONCLUSIONS
  These findings provide evidence that SIRT1 reduction links vascular senescence and inflammation to AAAs and that SIRT1 in vascular smooth muscle cells provides a therapeutic target for the prevention of AAA formation.
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Hou-Zao
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Jian-Fei
authors.initials: JF
authors.lastname: Pei
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Xu
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Tang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Wen-Yan
authors.initials: WY
authors.lastname: Fu
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Yan
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Xiao-Man
authors.initials: XM
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Zhu-Qin
authors.initials: ZQ
authors.lastname: Zhang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.).
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.). liudp@pumc.edu.cn mzou@gsu.edu.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.-Z.C., F.W., P.G., J.-F.P., Y.L., T.-T.X., X.T., W.-Y.F., J.L., Y.-F.Y., X.-M.W., L.H., Z.-Q.Z., R.Z., D.-P.L.); and Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (M.-H.Z.). liudp@pumc.edu.cn mzou@gsu.edu.
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
mesh_terms: D000375:Aging / Q000378:metabolism; D017542:Aneurysm, Ruptured / Q000209:etiology; D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D001025:Aortitis / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D002122:Calcium Chloride / Q000633:toxicity; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016328:NF-kappa B; D000804:Angiotensin II; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D002122:Calcium Chloride
keywords: SIRT1 protein, human; aging; angiotensin II; aortic aneurysm, abdominal; inflammation