Paradoxical Increase in Mortality and Rupture of Intracranial Aneurysms in Microsomal Prostaglandin E2 Synthase Type 1-Deficient Mice: Attenuation by Aspirin

Ricardo A Peña Silva; Ian J Mitchell; David K Kung; Lecia L Pewe; Manuel F Granja; John T Harty; Frank M Faraci; Donald D Heistad; David M Hasan

doi:10.1227/NEU.0000000000000883

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Paradoxical Increase in Mortality and Rupture of Intracranial Aneurysms in Microsomal Prostaglandin E2 Synthase Type 1-Deficient Mice: Attenuation by Aspirin

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Paradoxical Increase in Mortality and Rupture of Intracranial Aneurysms in Microsomal Prostaglandin E2 Synthase Type 1-Deficient Mice: Attenuation by Aspirin

Ricardo A Peña Silva, Ian J Mitchell, David K Kung, Lecia L Pewe, Manuel F Granja, John T Harty, Frank M Faraci, Donald D Heistad and David M Hasan

Neurosurgery, Vol.77(4), pp.613-620

10/2015

DOI: 10.1227/NEU.0000000000000883

PMCID: PMC4846385

PMID: 26134597

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https://www.ncbi.nlm.nih.gov/pmc/articles/4846385View

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Abstract

Inflammation plays an important role in formation and rupture of intracranial aneurysms. Expression of microsomal prostaglandin E2 (PGE2) synthase type 1 (mPGES-1) is increased in the wall of intracranial aneurysms in humans. PGE2, a by-product of mPGES-1, is associated with inflammation and cerebrovascular dysfunction. To test the hypothesis that deletion of mPGES-1 decreases the formation and rupture of intracranial aneurysms in a murine model. Intracranial aneurysms were induced in wild-type and mPGES-1 knockout (mPGES-1 KO) mice by using a combination of deoxycorticosterone acetate-salt-induced hypertension and intracranial injection of elastase in the basal cistern. Prevalence of aneurysms, subarachnoid hemorrhage, and mortality were assessed. We also tested the effects of administration of aspirin (6 mg/kg/d) by gavage and PGE2 (1 mg/kg/d) by subcutaneous infusion. Systolic blood pressure and prevalence of aneurysm were similar in wild-type and mPGES-1 KO mice. However, mortality and the prevalence of subarachnoid hemorrhage were markedly increased in mPGES-1 KO mice (P < .05). Bone marrow reconstitution studies suggest that mPGES-1 derived from leukocytes does not appear to increase rupture of intracranial aneurysms. Aspirin, but not PGE2, attenuated the increased mortality in mPGES-1 KO mice (P < .05). Vascular mPGES-1 plays a protective role in blood vessels and attenuates rupture of cerebral aneurysms. In contrast to effects on abdominal aneurysms, mPGES-1 deficiency is associated with an increase in rupture of cerebral aneurysms and mortality, which are attenuated by low-dose aspirin.

Aneurysm, Ruptured - mortality

Aneurysm, Ruptured - drug therapy

Humans

Mice, Inbred C57BL

Intracranial Aneurysm - mortality

Microsomes - enzymology

Intramolecular Oxidoreductases - deficiency

Mortality - trends

Mice, Knockout

Microsomes - drug effects

Aneurysm, Ruptured - enzymology

Animals

Prostaglandin-E Synthases

Aspirin - therapeutic use

Mice

Aspirin - pharmacology

Intracranial Aneurysm - drug therapy

Intracranial Aneurysm - enzymology

Details

Title: Subtitle: Paradoxical Increase in Mortality and Rupture of Intracranial Aneurysms in Microsomal Prostaglandin E2 Synthase Type 1-Deficient Mice: Attenuation by Aspirin
Creators: Ricardo A Peña Silva - Universidad de los Andes, Bogotá, Colombia; ‡Departments of Internal Medicine, §Neurosurgery, ¶Microbiology, and ‖Pharmacology, University of Iowa, Iowa City, Iowa
Ian J Mitchell
David K Kung
Lecia L Pewe
Manuel F Granja
John T Harty
Frank M Faraci
Donald D Heistad
David M Hasan
Resource Type: Journal article
Publication Details: Neurosurgery, Vol.77(4), pp.613-620
DOI: 10.1227/NEU.0000000000000883
PMID: 26134597
PMCID: PMC4846385
NLM abbreviation: Neurosurgery
ISSN: 0148-396X
eISSN: 1524-4040
Publisher: United States
Grant note: K08 NS082363 / NINDS NIH HHS P01 HL062984 / NHLBI NIH HHS I01 BX001399 / BLRD VA HL-62984 / NHLBI NIH HHS NS082363 / NINDS NIH HHS
Language: English
Date published: 10/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Pathology; Cardiovascular Medicine; Neuroscience and Pharmacology; Neurosurgery; Otolaryngology; Internal Medicine
Record Identifier: 9984040343302771

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