Silent Information Regulator 2 Homolog 1 Counters Cerebral Hypoperfusion Injury by Deacetylating Endothelial Nitric Oxide Synthase

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. (Stroke. 2014;45:3403-3411.)Key Words: carotid artery stenosis ◼ cerebral ischemia ◼ dementia ◼ endothelial nitric oxide synthase ◼ mouse ◼ SIRT1

The neuropathology and cerebrovascular mechanisms of dementia

“…To counteract these effects, new evidence shows that the upregulation of the deacetylase, sirtuin 1 can prevent cerebral hypoperfusion injury through the deacetylation and upregulation of endothelial nitric oxide synthase, thus offering a novel mechanism for the restoration of cerebral blood flow. 94 Furthermore, mitochondrial dysfunction is a well-established hallmark of A -induced neuronal toxicity. 95 Notably, microarray analysis revealed alterations in the genes relevant for hypoxic tolerance, energy/lipid metabolism, and mitochondrial bioenergetics/oxidative stress in 2-and 9-month-old spontaneously hypertensive rat model of hypertension.…”

Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease

“…64 Although the bilateral common carotid artery stenosis model cannot replicate small vessel vasculopathy or lacunar infarcts or model SVD, it possesses advantages in terms of reproducibility of WM pathology, characterized by BBB disruption, glial activation, oxidative stress, and oligodendrocyte loss. [65][66][67][68][69] Although clinically there is no direct evidence of an association between carotid stenosis and SVD or cognitive decline, once confounding risk factors are corrected for, 13,70,71 altered hemodynamics following bilateral common carotid artery stenosis results in opening of the endothelial tight junction only 2 hours after manipulation, which can be suppressed by matrix metalloproteinase 2 (MMP2) inhibitors. 66,68 MMP2, an extracellular matrix degradation enzyme, is also known to degrade the tight junction proteins ZO-1, claudin-5, and occludin, as well as induce BBB breakdown.…”

“…Несмотря на то что модель двустороннего стеноза общей сонной артерии не позволяет воспроизвести васкулопатию мелких сосудов, лакунарные инфаркты или поражения, характерные для БМЦС, она обладает преимуществами с точки зрения воспроизводимости патологии БВГМ, характеризующей-ся нарушением ГЭБ, активацией глии, оксидантным стрессом и гибелью олигодендроцитов [65][66][67][68][69]. Несмотря на отсутствие прямых клинических доказательств связи стеноза и БМЦС или развития когнитивных нарушений, при внесении поправок на вмешивающиеся факторы [13,70,71] нарушение гемодинамики в результате двусто-роннего стеноза приводит к открытию эндотелиальных плотных контактов только через 2 часа после манипуля-ций, которое можно подавить с помощью ингибиторов матричной металлопротеиназы-2 (MMP2) [66,68]. Также известно, что MMP2, фермент деградации внеклеточного матрикса, также разрушает белки плотных контактов ZO-1, клаудин-5 и окклюдин и индуцирует разрушение ГЭБ [72].…”

Neuronal SIRT1 (Silent Information Regulator 2 Homologue 1) Regulates Glycolysis and Mediates Resveratrol-Induced Ischemic Tolerance

“…What’s more, it is postulated that silent information regulator 2 homologue 1 (Sirt1) mediates at least some of these effects 4 . Adding to mechanistic complexity, Sirt1 is expressed in both brain and peripheral tissues and has been implicated in the regulation of inflammation 10 , cerebral blood flow 11 and neuronal functions 12 . It remains to be tested whether Sirt1 is essential for RPC-induced ischemic tolerance and if so, in which cell types.…”