Chalouhi Nohra, Starke Robert M, Correa Tatiana, Jabbour Pascal M, Zanaty Mario, Brown Robert D, Torner James C, Hasan David M
From the Department of Neurological Surgery, Thomas Jefferson University and Jefferson Hospital for Neuroscience, Philadelphia, PA (N.C., P.M.J.); Department of Neurological Surgery, University of Virginia School of Medicine, Charlottesville (R.M.S.); Carver College of Medicine (T.C.), Department of Neurological Surgery (M.Z., D.M.H.), and Department of Epidemiology, College of Public Health (J.C.T.), University of Iowa; and Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN (R.D.B.).
Hypertension. 2016 Aug;68(2):411-7. doi: 10.1161/HYPERTENSIONAHA.116.07515. Epub 2016 Jun 13.
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.
我们之前发现阿司匹林可降低人类脑动脉瘤破裂的风险。我们旨在评估人类脑动脉瘤对阿司匹林的反应是否存在性别差异，并在脑动脉瘤小鼠模型中证实这些观察结果。我们进行了一项来自颅内未破裂动脉瘤国际研究的巢式病例对照分析，以评估人类脑动脉瘤对阿司匹林的反应是否存在性别差异。随后在脑动脉瘤小鼠模型中进行了一系列实验。通过向小鼠脑基底池注射高血压药物和弹性蛋白酶来诱导动脉瘤形成。我们发现在颅内未破裂动脉瘤国际研究中，阿司匹林降低男性动脉瘤破裂风险的效果比女性更显著。在小鼠中，阿司匹林和环氧合酶 -2 抑制剂不影响脑动脉瘤的形成，但显著降低了破裂发生率。服用阿司匹林的雄性小鼠与雌性小鼠相比，破裂发生率显著更低。对脑动脉的基因表达分析显示雄性小鼠中 15 - 羟基前列腺素脱氢酶水平更高。与接受阿司匹林和 15 - 羟基前列腺素脱氢酶激动剂的雌性小鼠相比，接受阿司匹林和 15 - 羟基前列腺素脱氢酶抑制剂的雄性小鼠脑动脉瘤破裂率相似，这表明对阿司匹林的性别差异反应发生了逆转。阿司匹林可降低人和小鼠的动脉瘤破裂风险，部分是通过环氧合酶-2 途径。动物和人类研究的证据表明存在一致的性别差异效应。雌性小鼠中 15 - 羟基前列腺素脱氢酶的激活降低了破裂发生率，并消除了对阿司匹林的性别差异反应。
