title: Silent information regulator 2 homolog 1 counters cerebral hypoperfusion injury by deacetylating endothelial nitric oxide synthase.
abstract: OBJECTIVE
  Silent information regulator 2 homolog 1 (SIRT1) is a protein deacetylase that has been reported to suppress neurodegenerative and cardiovascular diseases in model organisms. We hypothesized that neurovascular protection is one of the diverse actions of SIRT1. This study was designed to determine whether SIRT1 protects against the consequences of cerebral hypoperfusion in vivo.
  
  
  METHODS
  Sirt1-overexpressing (Sirt1-Tg) mice driven by a prion promoter and their wild-type littermates were subjected to bilateral common carotid artery stenosis using external microcoils. Using Sirt1-Tg mice, we assessed the effect of SIRT1 on cerebral blood flow, cerebral angioarchitecture, histological and ultrastructural changes, and spatial working memory at several time points. We also evaluated the effects of preadministration of SIRT1 inhibitors or endothelial nitric oxide synthase inhibitors on cerebral blood flow after bilateral common carotid artery stenosis in Sirt1-Tg mice. Levels of acetylated and nonacetylated endothelial nitric oxide synthase were measured semiquantitatively with immunoblotting.
  
  
  RESULTS
  Cerebral hypoperfusion induced by bilateral common carotid artery stenosis caused memory impairment and histological changes in wild-type littermates. However, these phenotypes were rescued in Sirt1-Tg mice, where cerebral blood flow was maintained even poststenosis. Electron microscopic analyses showed irregularities in the vascular endothelia, such as tight junction openings in wild-type mice, which were absent in Sirt1-Tg littermates. Brain endothelial nitric oxide synthase was acetylated after cerebral hypoperfusion in wild-type littermates but remained unacetylated in Sirt1-Tg mice. Moreover, treatment with SIRT1 inhibitors and endothelial nitric oxide synthase inhibitors abolished the vasculoprotective effects of SIRT1.
  
  
  CONCLUSIONS
  Our results indicate that neurovascular endothelial SIRT1 potentiation upregulates the nitric oxide system and counters cerebral hypoperfusion injury. This novel cerebral blood flow-preserving mechanism offers potential molecular targets for future therapeutic intervention.
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.).
authors.forename: Yorito
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.).
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.).
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.).
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.).
authors.forename: Naoya
authors.initials: N
authors.lastname: Oishi
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.).
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yamahara
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.).
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nagatsuka
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.).
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.).
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.).
authors.forename: Hidenao
authors.initials: H
authors.lastname: Fukuyama
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.).
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: From the Department of Neurology (Y.H., R.T.) and Human Brain Research Center (N.O., H.F.), Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of Regenerative Medicine and Tissue Engineering (Y.H., Y.Y., K.Y., M.I.), Pathology (Y.O.), and Stroke and Cerebrovascular Diseases (K.N., M.I.), National Cerebral and Cardiovascular Center, Osaka, Japan; Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston (T.M.); CREST, Japan Science Technology Corporation, Saitama, Japan (R.T., M.K.); Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, United Kingdom (R.N.K.); and Division of Biological Science, Nagoya University Graduate School of Science, Nagoya, Japan (M.K.). ihara@ncvc.go.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
mesh_terms: D000107:Acetylation; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D056564:Sirtuin 1 / Q000096:biosynthesis*
chemical_list: D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: SIRT1; carotid artery stenosis; cerebral ischemia; dementia; endothelial nitric oxide synthase; mouse