A study to elucidate the mechanism by which the longevity gene product SIRT1 confers neuroprotection

2014 Fiscal Year Final Research Report

• Project/Area Number: 25640031
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: IHARA Masafumi 独立行政法人国立循環器病研究センター, 病院, 医長 (00372590)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 長寿遺伝子 / サーチュイン / SIRT1 / 血管性認知症 / 脳梗塞 / 脳卒中 / 内皮型一酸化窒素合成酵素 / 血液脳関門

Outline of Final Research Achievements

SIRT1 belongs to the sirtuin family of protein deacetylases which mediate extensions of lifespan and suppress cerebrovascular diseases in model organisms. We hypothesized that neurovascular protection incorporates the broad-range effects of SIRT1. To test this, we generated Sirt1-overexpressing (Sirt1-Tg) mice driven by a prion promoter to determine whether Sirt1-Tg mice protect consequences of cerebral hypoperfusion in vivo. Cerebral hypoperfusion induced by bilateral common carotid artery stenosis caused memory impairment and histological changes in wild-type mice. However, these phenotypes were rescued in Sirt1-Tg mice, where cerebral blood flow was maintained even poststenosis. Brain endothelial nitric oxide synthase was acetylated after cerebral hypoperfusion in wild-type littermates but remained unacetylated in Sirt1-Tg mice. Our results indicate that neurovascular endothelial SIRT1 potentiation upregulates the nitric oxide system and counters cerebral hypoperfusion injury.

Free Research Field

脳卒中学