Yorito Hattori1, Yoko Okamoto1, Takakuni Maki1, Yumi Yamamoto1, Naoya Oishi1, Kenichi Yamahara1, Kazuyuki Nagatsuka1, Ryosuke Takahashi1, Raj N Kalaria1, Hidenao Fukuyama1, Makoto Kinoshita1, Masafumi Ihara2. 1. 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.). 2. 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.
Abstract
BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: 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: Svetlana M Stamatovic; Gabriela Martinez-Revollar; Anna Hu; Jennifer Choi; Richard F Keep; Anuska V Andjelkovic Journal: Neurobiol Dis Date: 2018-09-06 Impact factor: 5.996
Authors: Ping Sun; Fan Bu; Jia-Wei Min; Yashasvee Munshi; Matthew D Howe; Lin Liu; Edward C Koellhoffer; Li Qi; Louise D McCullough; Jun Li Journal: Eur J Neurosci Date: 2018-11-29 Impact factor: 3.386
Authors: Robin Bonomi; Vadim Popov; Maxwell T Laws; David Gelovani; Anjoy Majhi; Aleksandr Shavrin; Xin Lu; Otto Muzik; Nashaat Turkman; Renshyan Liu; Thomas Mangner; Juri G Gelovani Journal: J Med Chem Date: 2018-08-13 Impact factor: 7.446