エストロゲン欠乏ラットのERαおよびSirt1の低下に伴うNLRP3/IL-1β/MMP-9経路の活性化と脳動脈瘤破裂との関連

Objective : Subarachnoid hemorrhage （SAH） due to rupture of intracranial aneurysm 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. We tested our hypothesis that, under estrogen-deficient conditions, activation of vascular nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 （NLRP3） inflammasomes via down-regulation of estrogen receptor （ER） and sirtuin1 （Sirt1） facilitates the ruptured intracranial aneurysms.
Methods : Ten-week-old female Sprague-Dawley rats with and without oophorectomy （OVX+ and OVX- rats, respectively） were subjected to hemodynamic changes and hypertension and fed a high-salt diet. Using human brain endothelial cells （HBECs） and smooth muscle cells （HBSMCs）, we tested the effect of estradiol, ER agonists.
Results : In OVX+ rats, the frequency of intracranial aneurysm rupture was significantly higher than in OVX- rats （p=0.03）. In the left posterior cerebral artery prone to rupture in OVX+ 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. Immunohistochemistry, the expression profiles of these proteins were 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 grown under estrogen-free conditions, the elevation of NLRP3, IL-1β, MMP-9, and the depletion of ERα and Sirt1, were counteracted by exposure to an ERα agonist, but not an ERβ agonist.
Conclusions : The down-regulation of ERα and Sirt1 by estrogen deficiency may contribute to the activation of the NLRP3/IL-1β/MMP-9 pathway, facilitating the rupture of intracranial aneurysms.