2022 Fiscal Year Final Research Report

Role of inflammasome activation and sirtuins in cerebral aneurysm rupture

Research Project

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Project/Area Number	20K09391
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 56010:Neurosurgery-related
Research Institution	The University of Tokushima
Principal Investigator	KANEMATSU Yasuhisa 徳島大学, 大学院医歯薬学研究部(医学域), 准教授 (90363142)
Co-Investigator(Kenkyū-buntansha)	高木康志徳島大学, 大学院医歯薬学研究部(医学域), 教授 (40312227) 八木謙次川崎医科大学, 医学部, 講師 (80551837) 多田恵曜徳島大学, 病院, 特任講師 (30547964) 島田健司徳島大学, 病院, 講師 (60624351) 高麗雅章徳島大学, 大学院医歯薬学研究部(医学域), 助教 (60794013) 宮本健志徳島大学, 大学院医歯薬学研究部(医学域), 徳島大学専門研究員 (80585000) 四方英二川崎医科大学, 医学部, 講師 (30813315)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	Inflammasome / NLRP3 / sirtuin / ERa / 脳動脈瘤破裂
Outline of Final Research Achievements	Subarachnoid hemorrhage due to intracranial aneurysm (IA) rupture is a devastating event. In estrogen deficient and hypertensive (OVX+/HT) aneurysm model rats, the frequency of IA rupture was significantly higher than in non OVX/HT rats. In the left posterior cerebral artery prone to rupture in OVX+/HT rats, the mRNA levels of estrogen receptor (ER)αand sirtuin (Sirt1) were decreased, and the mRNA levels of NLRP3 inflammasome and interleukin-1β (IL-1β), and matrix metalloproteinase 9 (MMP-9) were elevated. Treatment with an ER modulator, bazedoxifene normalized the expression of these proteins and improved SAH-free survival. In human cerebral vascular cell lines. the depletion of ERα and Sirt1 and the accumulation of NLRP3 were counteracted by estradiol or an ERαagonist. This work represents that the depletion of ERα and Sirt1 may contribute to activation of the NLRP3/IL-1β/MMP-9 pathway, facilitating the rupture of IAs under E2- condition.
Free Research Field	脳神経外科関連
Academic Significance and Societal Importance of the Research Achievements	閉経期以後に脳動脈瘤破裂をきたし易い女性のERαを介した作用について培養した脳血管内皮細胞又は平滑筋細胞を用い、エストロゲンの存在／非存在下で、エストロゲン受容体βの発現と炎症性変化の指標としてNLRP3、その防御的役割を果たす可能性のあるsirt1の発現を解析, 17β-estradiol, ERα作動薬のPPT(4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol)依存的、エストロゲン受容体ERα作動薬DPN (Diarylpropionitrile)非依存的に抗炎症作用により血管保護的に作用する事を実証し、臨床応用が期待される。