Sex differences in the response to activation of the poly (ADP-ribose) polymerase pathway after experimental stroke.
Sex differences in the response to activation of the poly (ADP-ribose) polymerase pathway after experimental stroke.
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DOI：
10.1016/j.expneurol.2009.02.012
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发表时间：
2009-05
影响因子：
5.3
通讯作者：
McCullough, Louise D.
中科院分区：
文献类型：
--
作者：
Yuan, Mike;Siegel, Chad;Zeng, Zhiyuan;Li, Jun;Liu, Fudong;McCullough, Louise D.
关键词：
越来越多的人认识到，中风后的组织和功能结果是由生物性别决定的。新出现的数据表明，缺血细胞死亡途径是性别二态的。减少神经元一氧化氮(NO)或多聚ADP核糖聚合酶(PARP-1)的激活只保护男性的大脑，相反地增强女性的缺血性损伤。在这项研究中，我们检测了NO/PARP激活的下游介质，以探讨缺血性二型性的可能介质。在中风后，野生型男性和女性的凋亡诱导因子(AIF)的核转位是相同的，不受雌激素暴露的影响。PARP1缺失导致卒中诱导的多聚(ADP-核糖)聚合酶(PAR)的形成和AIF易位在两性中显著减少，然而缺血性损害仅在男性中减少。随后对AIF缺陷的小丑小鼠的研究表明，与雄性野生型小鼠相比，雄性小丑小鼠的PAR形成更少，AIF易位减少，缺血损伤也更少。相比之下，雌性小丑小鼠没有基因缺失的神经保护作用，尽管PAR形成和AIF易位显著减少。虽然这种细胞死亡途径在缺血后在两性中都有同等的激活，但有害的影响只存在于男性。AIF易位和PAR的形成不会介导女性大脑的缺血性损伤，因此旨在降低PARP1活性的药物不太可能对女性有益。
It is increasingly recognized that histological and functional outcomes after stroke are shaped by biologic sex. Emerging data suggests that ischemic cell death pathways are sexually dimorphic. Reducing neuronal nitric oxide (NO) or poly-ADP ribose polymerase (PARP-1) activation protects only the male brain, and paradoxically enhances ischemic injury in females. In this study, we examined downstream mediators of NO/PARP activation to investigate possible mediators of ischemic sexual dimorphism. Nuclear translocation of Apoptosis Inducing Factor (AIF) was equivalent in wild-type males and females after stroke and was unaffected by estrogen exposure. Deletion of PARP1 led to a dramatic reduction in stroke-induced poly(ADP-ribose) polymerase (PAR) formation and AIF translocation in both sexes, yet ischemic damage was reduced only in males. Subsequent examination of AIF-deficient Harlequin mice demonstrated that male Harlequin mice had less PAR formation, reduced AIF translocation and less ischemic damage than male wild-type mice. In contrast, female Harlequin mice had no neuroprotective effect of gene deletion despite robust reductions in PAR formation and AIF translocation. Although equivalent activation of this cell death pathway occurs in both sexes after ischemia, detrimental effects are only present in males. AIF translocation and PAR formation do not mediate ischemic injury in the female brain, therefore agents designed to reduce PARP1 activation are unlikely to benefit females.
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影响因子：
8.3
作者：
Hurn, PD;Vannucci, SJ;Hagberg, H
通讯作者：
Hagberg, H
DOI：
10.1093/jnen/62.4.329
发表时间：
2003-04-01
影响因子：
3.2
作者：
Ferrer, I;Planas, AM
通讯作者：
Planas, AM
影响因子：
4.4
作者：
Chan, PH
通讯作者：
Chan, PH
影响因子：
9.9
作者：
Fullerton, HJ;Wu, YW;Johnston, SC
通讯作者：
Johnston, SC
DOI：
10.1073/pnas.0406182101
发表时间：
2004-12-21
影响因子：
11.1
作者：
Koh, DW;Lawler, AM;Dawson, TM
通讯作者：
Dawson, TM