Yamaguchi, Tadashi Tokushima University
Miyamoto, Takeshi Tokushima University
Shikata, Eiji Tokushima University
Yamaguchi, Izumi Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Shimada, Kenji Tokushima University Tokushima University Educator and Researcher Directory
Tada, Yoshiteru Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Korai, Masaaki Tokushima University Tokushima University Educator and Researcher Directory
Kitazato, Keiko T. Tokushima University
Kanematsu, Yasuhisa Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Takagi, Yasushi Tokushima University Tokushima University Educator and Researcher Directory
Thesis or Dissertation
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.
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.
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.
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.
Journal of Neurosurgery
American Association of Neurological Surgeons
|DOI (Published Version)
|URL ( Publisher's Version )
k3665_abstract.pdf 132 KB
k3665_review.pdf 112 KB
k3665_fulltext.pdf 7.92 MB
|MEXT report number
Doctor of Medical Science