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ID 117700
タイトル別表記
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
著者
山口, 真司 徳島大学大学院医学研究科(医学専攻)
Shikata, Eiji Tokushima University
Kitazato, Keiko T. Tokushima University
キーワード
Estrogen deficiency
estrogen receptor
intracranial aneurysm
NLRP3 inflammasome
Sirt1
vascular disorders
資料タイプ
学位論文
抄録
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.
掲載誌名
Journal of Neurosurgery
ISSN
00223085
19330693
cat書誌ID
AA00703389
出版者
American Association of Neurological Surgeons
138
1
開始ページ
191
終了ページ
198
発行日
2022-05-20
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Tadashi Yamaguchiの学位論文として提出され,学位審査・授与の対象となっている。
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3665号
学位記番号
甲医第1547号
学位授与年月日
2022-10-27
学位名
博士(医学)
学位授与機関
徳島大学
部局
病院
医学系