Sex differences in caspase activation after stroke.
Sex differences in caspase activation after stroke.
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DOI：
10.1161/strokeaha.108.538686
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发表时间：
2009-05
期刊：
影响因子：
8.3
通讯作者：
McCullough LD
中科院分区：
文献类型：
--
作者：
Liu F;Li Z;Li J;Siegel C;Yuan R;McCullough LD
在过去的五年中，实验数据显示，缺血诱导的细胞死亡途径在男性和女性中可能不同。雄性的细胞死亡是由聚（ADP-核糖）聚合酶（PARP）激活和凋亡诱导因子（AIF）的核转位引发的。我们以前已经表明，干扰这一途径有利于男性，但不是女性实验性中风后。相反，caspase激活可能是女性缺血损伤后激活的主要途径。本研究的目的是检查是否存在性别差异，在成年小鼠脑卒中后caspase激活，并确定是否干扰脑卒中诱导的caspase激活优先保护女性。通过可逆性大脑中动脉闭塞（MCAO; 90分钟）在两种性别的年轻和老龄C57 BL 6小鼠中诱导局灶性中风。在再灌注时给予泛半胱天冬酶抑制剂喹啉-Val-Asp（Ome）-CH 2-O-苯氧基（Q-VD-OPh）。在MCAO后48小时评估组织学结局。使用单独的组群进行关键细胞死亡蛋白的蛋白质分析，包括半胱天冬酶-3、半胱天冬酶-8、细胞色素C和凋亡诱导因子（AIF）。与溶剂处理的小鼠相比，药物处理的雌性小鼠中风后的梗死体积显着减少，神经功能障碍得到改善。Q-VD-OPh给药对雄性小鼠无影响。女性脑卒中后细胞色素C表达和核caspase-8水平升高。雌性小鼠在MCAO后细胞色素C的早期释放和增强的半胱天冬酶激活。胱天蛋白酶抑制有益于女性，但不是男性。在对缺血性损伤的反应和神经保护剂的疗效方面都存在性别差异。
Over the past five years, experimental data has emerged that ischemia-induced cell death pathways may differ in males and females. Cell death in males is triggered by Poly(ADP-ribose) polymerase (PARP) activation and nuclear translocation of apoptosis-inducing factor (AIF). We have previously shown that interference with this pathway benefits males but not females after an experimental stroke. In contrast caspase activation may be the major pathway activated after ischemic injury in females. The aim of this study is to examine whether sex differences exist in caspase activation in adult mice after stroke and to determine if interference with stroke-induced caspase activation preferentially protects females. Focal stroke was induced by reversible middle cerebral artery occlusion (MCAO; 90 minutes) in young and aging C57BL6 mice of both sexes. The pan-caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VD-OPh) was administered at reperfusion. Histological outcomes was assessed 48 hours after MCAO. Separate cohorts were utilized for protein analysis of key cell death proteins including caspase-3, caspase-8, cytochrome C and Apoptosis Inducing Factor (AIF). Drug-treated female mice had significantly decreased infarct volumes and improved neurological deficits after stroke compared to vehicle-treated mice. Q-VD-OPh administration had no effect in male mice. The expression of cytochrome C and nuclear caspase-8 levels were increased in females after stroke. Female mice had an early release of cytochrome C and enhanced caspase activation after MCAO. Caspase inhibition benefited females but not males. Sex differences exist in both the response to ischemic injury and the efficacy of neuroprotective agents.