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Differential Sex Response to Aspirin in Decreasing Aneurysm Rupture in Humans and Mice
Journal article   Open access   Peer reviewed

Differential Sex Response to Aspirin in Decreasing Aneurysm Rupture in Humans and Mice

Nohra Chalouhi, Robert M Starke, Tatiana Correa, Pascal M Jabbour, Mario Zanaty, Robert D Brown Jr, James C Torner and David M Hasan
Hypertension (Dallas, Tex. 1979), Vol.68(2), pp.411-417
08/2016
DOI: 10.1161/HYPERTENSIONAHA.116.07515
PMCID: PMC4945417
PMID: 27296993
url
https://doi.org/10.1161/HYPERTENSIONAHA.116.07515View
Published (Version of record) Open Access

Abstract

We previously found that aspirin decreases the risk of cerebral aneurysm rupture in humans. We aim to assess whether a sex differential exists in the response of human cerebral aneurysms to aspirin and confirm these observations in a mouse model of cerebral aneurysm. A nested case-control analysis from the International Study of Unruptured Intracranial Aneurysms was performed to assess whether a sex differential exists in the response of human cerebral aneurysms to aspirin. A series of experiments were subsequently performed in a mouse model of cerebral aneurysms. Aneurysms were induced with hypertension and elastase injection into mice basal cisterns. We found that aspirin decreased the risk of aneurysm rupture more significantly in men than in women in the International Study of Unruptured Intracranial Aneurysms. In mice, aspirin and cyclooxygenase-2 inhibitor did not affect cerebral aneurysm formation but significantly decreased the incidence of rupture. The incidence of rupture was significantly lower in male versus female mice on aspirin. Gene expression analysis from cerebral arteries showed higher 15-hydroxyprostaglandin dehydrogenase levels in male mice. The rate of cerebral aneurysm rupture was similar in male mice receiving aspirin and 15-hydroxyprostaglandin dehydrogenase inhibitor compared with females receiving aspirin and 15-hydroxyprostaglandin dehydrogenase agonist, signaling a reversal of the sex-differential response to aspirin. Aspirin decreases aneurysm rupture in human and mice, in part through cyclooxygenase-2 pathways. Evidence from animal and human studies suggests a consistent differential effect by sex. 15-Hydroxyprostaglandin dehydrogenase activation in females reduces the incidence of rupture and eliminates the sex-differential response to aspirin.
 Follow-Up Studies Humans Aneurysm, Ruptured - prevention & control Aspirin - pharmacokinetics Male Intracranial Aneurysm - prevention & control Hydroxyprostaglandin Dehydrogenases - metabolism Aspirin - administration & dosage Incidence Subarachnoid Hemorrhage - prevention & control Female Disease Models, Animal Risk Factors Cyclooxygenase Inhibitors - administration & dosage Intracranial Aneurysm - metabolism Cyclooxygenase Inhibitors - pharmacokinetics Hydroxyprostaglandin Dehydrogenases - antagonists & inhibitors Animals Cerebral Arteries - metabolism Aneurysm, Ruptured - metabolism Cerebral Arteries - pathology Cyclooxygenase 2 - metabolism Sex Factors Subarachnoid Hemorrhage - etiology Mice Aneurysm, Ruptured - pathology Intracranial Aneurysm - pathology

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