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

Tadashi YamaguchiDepartment of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

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Takeshi MiyamotoDepartment of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

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Eiji ShikataDepartment of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

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Izumi YamaguchiDepartment of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

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Kenji ShimadaDepartment of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

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Kenji YagiDepartment of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

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Yoshiteru TadaDepartment of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

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Masaaki KoraiDepartment of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

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Keiko T. KitazatoDepartment of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

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Yasuhisa KanematsuDepartment of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

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Yasushi TakagiDepartment of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

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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.

ABBREVIATIONS

Ang II = angiotensin II; BZA = bazedoxifene; DPN = diarylpropionitrile; eNOS = endothelial nitric oxide synthase; ER = estrogen receptor; HBEC = human brain endothelial cell; HBSMC = human brain smooth muscle cell; HT = hypertension; IA = intracranial aneurysm; IL-1β = interleukin-1β; MMP-9 = matrix metalloproteinase 9; OVX+ = oophorectomized; OVX− = nonoophorectomized; NLRP3 = nucleotide-binding oligomerization domain–like receptor family pyrin domain–containing 3; NOX4 = NADPH oxidase 4; PCA = posterior cerebral artery; PPT = propylpyrazoletriol; SAH = subarachnoid hemorrhage; Sirt1 = sirtuin 1.

Supplementary Materials

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Figure from Ramos et al. (pp 95–103).

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