MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia
MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia
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DOI：
10.1210/en.2006-1137
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发表时间：
2007-03-01
期刊：
影响因子：
4.8
通讯作者：
Etgen, Anne M.
中科院分区：
文献类型：
--
作者：
Jover-Mengual, Teresa;Zukin, R. Suzanne;Etgen, Anne M.
激素治疗对绝经后妇女全脑缺血后遗症的重要性仍有争议。在心脏骤停或心脏手术过程中出现的全脑缺血导致海马CA 1区神经元高度选择性的延迟性死亡。外源性雌二醇改善雄性和雌性啮齿动物全脑缺血诱导的神经元死亡和认知障碍。然而，雌激素干预全脑缺血诱导的细胞凋亡的分子机制尚不清楚。在这里，我们表明，雌二醇通过经典的雌激素受体，IGF-I受体，ERK/MAPK信号级联保护CA 1神经元在卵巢切除雌性大鼠和沙鼠。我们证明，全脑缺血促进ERK 1和转录因子cAMP-反应元件结合蛋白CREB的早期去磷酸化和失活，随后下调抗凋亡蛋白Bcl-2（雌二醇和CREB的已知基因靶点），并激活caspase-3。雌二醇治疗增加海马CA 1区ERK 1和ERK 2的基础磷酸化，并防止缺血诱导的ERK 1和CREB的去磷酸化和失活，Bcl-2的下调和caspase死亡级联的激活。ERK/MAPK信号通路对CREB的激活和神经元的存活至关重要，而雌二醇对Bcl-2水平的影响不依赖于ERK。这些发现支持了一种模型，即雌二醇通过经典的雌激素受体和IGF-I受体发挥作用，这些受体聚集在ERK/MAPK信号转导和CREB的激活上，以促进神经元在全脑缺血时的存活。
The importance of hormone therapy in affording protection against the sequelae of global ischemia in postmenopausal women remains controversial. Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous estradiol ameliorates global ischemia-induced neuronal death and cognitive impairment in male and female rodents. However, the molecular mechanisms by which estrogens intervene in global ischemia-induced apoptotic cell death are unclear. Here we show that estradiol acts via the classical estrogen receptors, the IGF-I receptor, and the ERK/MAPK signaling cascade to protect CA1 neurons in ovariectomized female rats and gerbils. We demonstrate that global ischemia promotes early dephosphorylation and inactivation of ERK1 and the transcription factor cAMP-response element binding protein CREB), subsequent down-regulation of the antiapoptotic protein Bcl-2, a known gene target of estradiol and CREB, and activation of caspase-3. Estradiol treatment increases basal phosphorylation of both ERK1 and ERK2 in hippocampal CA1 and prevents ischemia-induced dephosphorylation and inactivation of ERK1 and CREB, down-regulation of Bcl-2 and activation of the caspase death cascade. Whereas ERK/MAPK signaling is critical toCREBactivation and neuronal survival, the impact of estradiol on Bcl-2 levels is ERK independent. These findings support a model whereby estradiol acts via the classical estrogen receptors and IGF-I receptors, which converge on activation of ERK/MAPK signaling and CREB to promote neuronal survival in the face of global ischemia.