Dataset Information

Somatic Variants in SVIL in Cerebral Aneurysms.

ABSTRACT:

Background and objectives

While somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms.

Methods

We performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results.

Results

Somatic variants involved in supervillin (SVIL) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in the SVIL gene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown of SVIL via the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found that SVIL regulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway.

Discussion

We propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants in SVIL result in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms.

SUBMITTER: Lai PMR

PROVIDER: S-EPMC9720733 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Somatic Variants in SVIL in Cerebral Aneurysms.

Lai Pui Man Rosalind PMR Ryu Jee-Yeon JY Park Sang-Cheol SC Gross Bradley A BA Dickinson Lawrence D LD Dagen Sarajune S Aziz-Sultan Mohammad Ali MA Boulos Alan S AS Barrow Daniel L DL Batjer H Hunt HH Blackburn Spiros S Chang Edward F EF Chen P Roc PR Colby Geoffrey P GP Cosgrove Garth Rees GR David Carlos A CA Day Arthur L AL Frerichs Kai U KU Niemela Mika M Ojemann Steven G SG Patel Nirav J NJ Shi Xiangen X Valle-Giler Edison P EP Wang Anthony C AC Welch Babu G BG Zusman Edie E EE Weiss Scott T ST Du Rose R

Neurology. Genetics 20221128 6

<h4>Background and objectives</h4>While somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms.<h4>Methods</h4>We performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results.<h4>Results</h4>Somatic variant ...[more]

PMID: 36475054

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Project description:Background and purposeCerebral aneurysm (CA) affects 3% of the population and is associated with hemodynamic stress and inflammation. Myeloperoxidase, a major oxidative enzyme associated with inflammation, is increased in patients with CA, but whether myeloperoxidase contributes to CA is not known. We tested the hypotheses that myeloperoxidase is increased within human CA and is critical for formation and rupture of CA in mice.MethodsBlood was drawn from the lumen of CAs and femoral arteries of 25 patients who underwent endovascular coiling of CA, and plasma myeloperoxidase concentrations were measured with ELISA. Effects of endogenous myeloperoxidase on CA formation and rupture were studied in myeloperoxidase knockout mice and wild-type (WT) mice using an angiotensin II-elastase induction model of CA. In addition, effects of myeloperoxidase on inflammatory gene expression in endothelial cells were analyzed.ResultsPlasma concentrations of myeloperoxidase were 2.7-fold higher within CA than in femoral arterial blood in patients with CA. myeloperoxidase-positive cells were increased in aneurysm tissue compared with superficial temporal artery of patients with CA. Incidence of aneurysms and subarachnoid hemorrhage was significantly lower in myeloperoxidase knockout than in WT mice. In cerebral arteries, proinflammatory molecules, including tumor necrosis factor-α, cyclooxygenase-2 (COX2), chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (C motif) ligand (XCL1), matrix metalloproteinase (MMP) 8, cluster of differentiation 68 (CD68), and matrix metalloproteinase 13, and leukocytes were increased, and α-smooth muscle actin was decreased, in WT but not in myeloperoxidase knockout mice after induction of CA. Myeloperoxidase per se increased expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in endothelial cells.ConclusionsThese findings suggest that myeloperoxidase may contribute importantly to formation and rupture of CA.

Dataset Information

Somatic Variants in SVIL in Cerebral Aneurysms.

Background and objectives

Methods

Results

Discussion

Publications

Somatic Variants in SVIL in Cerebral Aneurysms.

Similar Datasets

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