Activation of the NLRP3/IL-1β/MMP-9 pathway and intracranial aneurysm rupture associated with the depletion of ERα and Sirt1 in oophorectomized rats

• Material Type: 博士論文
• Title: Activation of the NLRP3/IL-1β/MMP-9 pathway and intracranial aneurysm rupture associated with the depletion of ERα and Sirt1 in oophorectomized rats
• Author/Editor: Yamaguchi, Tadashi; Miyamoto, Takeshi; Shikata, Eiji; Yamaguchi, Izumi; Shimada, Kenji; Yagi, Kenji; Tada, Yoshiteru; Korai, Masaaki; Kitazato, Keiko T.; Kanematsu, Yasuhisa; Takagi, Yasushi
• Author Heading: Yamaguchi, Tadashi; Miyamoto, Takeshi; Shikata, Eiji; Yamaguchi, Izumi; Shimada, Kenji; Yagi, Kenji; Tada, Yoshiteru; Korai, Masaaki; Kitazato, Keiko T.; Kanematsu, Yasuhisa; Takagi, Yasushi
• Publication, Distribution, etc.: American Association of Neurological Surgeons
• Publication Date: 2022-05-20
• Publication Date (W3CDTF): 2022-05-20
• Alternative Title: 卵巣摘出ラットにおけるERαおよびSirt1の減少に伴うNLRP3/IL-1β/MMP-9経路の活性化と脳動脈瘤破裂の関連
• Periodical title: Journal of Neurosurgery
• No. or year of volume/issue: 138 1
• Volume: 138
• Issue: 1
• Pages: 191-198
• ISSN (Periodical Title): ISSN : 0022-3085; ISSN : 1933-0693
• Degree grantor/type: 徳島大学
• Date Granted: 2022-10-27
• Dissertation Number: 甲第3665号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: Estrogen deficiency; estrogen receptor; intracranial aneurysm; NLRP3 inflammasome; Sirt1; vascular disorders
• Target Audience: 一般
• Note (General): OBJECTIVE Subarachnoid hemorrhage (SAH) due to intracranial aneurysm (IA) rupture is often a devastating event. Since the incidence of SAH increases especially in menopause, it is crucial to clarify the detailed pathogenesis of these events. The activation of vascular nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes has been studied in ischemic stroke and cardiovascular disease. However, the role of NLRP3 in IA rupture still needs to be explained. The authors sought to test their hypothesis that, under estrogen-deficient conditions, activation of NLRP3 inflammasomes via downregulation of the estrogen receptor (ER) facilitates IA rupture. METHODS Ten-week-old female Sprague Dawley rats with and without oophorectomy were subjected to hemodynamic changes and hypertension (OVX+/HT and OVX-/HT, respectively) and fed a high-salt diet. Separately, using human brain endothelial cells (HBECs) and human brain smooth muscle cells (HBSMCs), the authors tested the effect of NLRP3 under estrogen-free conditions and in the presence of estradiol or of ER agonists. RESULTS In OVX+/HT rats, the frequency of IA rupture was significantly higher than in OVX-/HT rats (p = 0.03). In the left posterior cerebral artery prone to rupture in OVX+/HT rats, the levels of the mRNAs encoding ERα and Sirt1, but not of that encoding ERβ, were decreased, and the levels of the mRNAs encoding NLRP3, interleukin-1β (IL-1β), and matrix metalloproteinase 9(MMP-9) were elevated. Immunohistochemical analysis demonstrated that the expression profiles of these proteins correlated with their mRNA levels. Treatment with an ER modulator, bazedoxifene, normalized the expression profiles of these proteins and improved SAH-free survival. In HBECs and HBSMCs under estrogen-free conditions, the depletion of ERα and Sirt1 and the accumulation of NLRP3 were counteracted by exposure to estradiol or to an ERα agonist but not to an ERβ agonist. CONCLUSIONS To the authors’ knowledge, this work represents the first demonstration that, in an aneurysm model under estrogen-deficient conditions, the depletion of ERα and Sirt1 may contribute to activation of the NLRP3/IL-1β/MMP-9 pathway, facilitating the rupture of IAs in the estrogen-deficient rat IA rupture model.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Related Material (DOI): 10.3171/2022.4.JNS212945
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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http://repo.lib.tokushima-u.ac.jp/files/public/11/117700/20221111115707976990/k3665_abstract.pdf fulltext

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