Dataset Information

Critical role of TNF-? in cerebral aneurysm formation and progression to rupture.

ABSTRACT:

Background

Alterations in TNF-? expression have been associated with cerebral aneurysms, but a direct role in formation, progression, and rupture has not been established.

Methods

Cerebral aneurysms were induced through hypertension and a single stereotactic injection of elastase into the basal cistern in mice. To test the role of TNF-? in aneurysm formation, aneurysms were induced in TNF-? knockout mice and mice pretreated with the synthesized TNF-? inhibitor 3,6'dithiothalidomide (DTH). To assess the role of TNF-? in aneurysm progression and rupture, DTH was started 6 days after aneurysm induction. TNF-? expression was assessed through real-time PCR and immunofluorescence staining.

Results

TNF-? knockout mice and those pre-treated with DTH had significantly decreased incidence of aneurysm formation and rupture as compared to sham mice. As compared with sham mice, TNF-? protein and mRNA expression was not significantly different in TNF-? knockout mice or those pre-treated with DTH, but was elevated in unruptured and furthermore in ruptured aneurysms. Subarachnoid hemorrhage (SAH) occurred between 7 and 21 days following aneurysm induction. To ensure aneurysm formation preceded rupture, additional mice underwent induction and sacrifice after 7 days. Seventy-five percent had aneurysm formation without evidence of SAH. Initiation of DTH treatment 6 days after aneurysm induction did not alter the incidence of aneurysm formation, but resulted in aneurysmal stabilization and a significant decrease in rupture.

Conclusions

These data suggest a critical role of TNF-? in the formation and rupture of aneurysms in a model of cerebral aneurysm formation. Inhibitors of TNF-? could be beneficial in preventing aneurysmal progression and rupture.

SUBMITTER: Starke RM

PROVIDER: S-EPMC4022343 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Publications

Critical role of TNF-α in cerebral aneurysm formation and progression to rupture.

Starke Robert M RM Chalouhi Nohra N Jabbour Pascal M PM Tjoumakaris Stavropoula I SI Gonzalez L Fernando LF Rosenwasser Robert H RH Wada Kosuke K Shimada Kenji K Hasan David M DM Greig Nigel H NH Owens Gary K GK Dumont Aaron S AS

Journal of neuroinflammation 20140416

<h4>Background</h4>Alterations in TNF-α expression have been associated with cerebral aneurysms, but a direct role in formation, progression, and rupture has not been established.<h4>Methods</h4>Cerebral aneurysms were induced through hypertension and a single stereotactic injection of elastase into the basal cistern in mice. To test the role of TNF-α in aneurysm formation, aneurysms were induced in TNF-α knockout mice and mice pretreated with the synthesized TNF-α inhibitor 3,6'dithiothalidomid ...[more]

PMID: 24739142

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Project description:Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor ? (PPAR?) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPAR? promote atherosclerosis and vascular dysfunction. We tested the role of PPAR? in aneurysm formation and rupture. Aneurysms were induced with a combination of systemic infusion of angiotensin-II and local injection of elastase in (1) mice that received the PPAR? antagonist GW9662 or the PPAR? agonist pioglitazone, (2) mice carrying dominant-negative PPAR? mutations in endothelial or smooth muscle cells, and (3) mice that received the Cullin inhibitor MLN4924. Incidence of aneurysm formation, rupture, and mortality was quantified. Cerebral arteries were analyzed for expression of Cullin3, Kelch-like ECH-associated protein 1, nuclear factor (erythroid-derived 2)-like 2, NAD(P)H dehydrogenase (quinone)1 (NQO1), and inflammatory marker mRNAs. Neither pioglitazone nor GW9662 altered the incidence of aneurysm formation. GW9662 significantly increased the incidence of aneurysm rupture, whereas pioglitazone tended to decrease the incidence of rupture. Dominant-negative endothelial-specific PPAR? did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPAR? resulted in an increase in aneurysm formation (P<0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPAR?, but not dominant-negative endothelial-specific PPAR?, resulted in significant decreases in expression of genes encoding Cullin3, Kelch-like ECH-associated protein 1, and nuclear factor (erythroid-derived 2)-like 2, along with significant increases in tumor necrosis factor-?, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligand 1, CD68, matrix metalloproteinase-3, -9, and -13. MLN4924 did not alter incidence of aneurysm formation, but increased the incidence of rupture (P<0.05). In summary, endogenous PPAR?, specifically smooth muscle PPAR?, plays an important role in protecting from formation and rupture of experimental cerebral aneurysms in mice.