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

書誌事項

タイトル
Activation of the NLRP3/IL-1β/MMP-9 pathway and intracranial aneurysm rupture associated with the depletion of ERα and Sirt1 in oophorectomized rats
タイトル別名
  • 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
著者別名
  • ヤマグチ, タダシ
  • Yamaguchi, Tadashi
著者
宮本, 健志
著者別名
  • ミヤモト, タケシ
  • Miyamoto, Takeshi
著者
シカタ, エイジ
著者別名
  • Shikata, Eiji
著者
山口, 泉
著者別名
  • ヤマグチ, イヅミ
  • Yamaguchi, Izumi
著者
島田, 健司
著者別名
  • シマダ, ケンジ
  • Shimada, Kenji
著者
八木, 謙次
著者別名
  • ヤギ, ケンジ
  • Yagi, Kenji
著者
多田, 恵曜
著者別名
  • タダ, ヨシテル
  • Tada, Yoshiteru
著者
高麗, 雅章
著者別名
  • コウライ, マサアキ
  • Korai, Masaaki
著者
キタザト, ケイコ
著者別名
  • Kitazato, Keiko T.
著者
兼松, 康久
著者別名
  • カネマツ, ヤスヒサ
  • Kanematsu, Yasuhisa
著者
高木, 康志
著者別名
  • タカギ, ヤスシ
  • Takagi, Yasushi
学位授与大学
徳島大学
取得学位
博士(医学)
学位授与番号
甲医第1547号
学位授与年月日
2022-10-27

説明

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.

詳細情報 詳細情報について

問題の指摘

ページトップへ