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

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.

Keywords: aneurysm; aspirin; inflammation; sex; subarachnoid hemorrhage.

Figure 1

CAs were induced in 56 C57BL/6J mice divided equally into mice receiving vehicle only (DMSO), aspirin (25 mg/kg/day IP), Cox-1 inhibitor (Sc-560 10mg/kg/day IP), and Cox-2 inhibitor (NS-398 20 mg/kg/day IP). (1A, upper left graph) Aspirin and Cox-2 inhibitor did not alter the rate of CA formation in mice. (1B, upper right graph) Aspirin and Cox-2 inhibitor significantly reduced the risk of SAH in mice. (1C, lower graph) Aspirin and Cox-2 inhibitor significantly prolonged asymptomatic survival in mice. * indicates statistically significant difference.

Figure 2

Aneurysms were induced in 36 Cox-1 knockout mice and divided into three equal groups: 1) Cox-1 KO mice receiving vehicle (DMSO) and serving as a control 2) Cox-1 KO mice receiving aspirin (25 mg/kg/day IP), and 3) Cox-1 KO mice receiving Cox-2 inhibitor. Aspirin and Cox-2 inhibitor did not affect the incidences of CA formation and rupture in Cox-1 KO mice. Cox-2 inhibitor increased asymptomatic survival rate. * indicates statistically significant difference.

Figure 3

CAs were induced in 16 mPGES-1 KO mice and divided into 2 groups: 1) 8 mice receiving vehicle, and 2) 8 mPGES-1 KO mice receiving a Cox-2 inhibitor (NS-398 20 mg/kg/day IP). Cox-2 inhibitor did not alter the incidences of CA formation and rupture in PGES-1 KO mice. There was a trend towards increased asymptomatic survival in PGES-1 KO mice receiving a Cox-2 inhibitor. * indicates statistically significant difference.

Figure 4

CAs were induced in 2 groups of C57BL/6J mice: 1) 12 male mice receiving aspirin (25 mg/kg/day IP), and 2) 12 female mice receiving aspirin (25 mg/kg/day IP). Male mice treated with aspirin had lower rates of aneurysm rupture compared with female mice. CAs were then induced in 2 groups of C57BL/6J mice: 1) 12 male mice receiving aspirin and 15-PGDH inhibitor (Cay10638; 1mg/kg/day IP), and 2) 12 female mice receiving aspirin and 15-PGDH agonist (CDDO-Me, 250 ng per day IP). The rate of CA rupture/SAH was similar between the 2 groups, indicating a reversal of the sex differential response to aspirin. * indicates statistically significant difference.