Estrogen and Bcl-2: Gene induction and effect of transgene in experimental stroke
Estrogen and Bcl-2: Gene induction and effect of transgene in experimental stroke
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DOI：
10.1523/jneurosci.21-19-07543.2001
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发表时间：
2001-10-01
影响因子：
5.3
通讯作者：
Hurn, PD
中科院分区：
文献类型：
--
作者：
Alkayed, NJ;Goto, S;Hurn, PD
产生内源性雌激素的雌性啮齿动物与雄性啮齿动物相比，免受中风损害。这种自然保护在卵巢切除或生殖衰老后就失去了。本研究的目的是确定雌激素是否通过增加Bcl-2的表达来减少缺血后早期神经元损伤和细胞损失。将雄性大鼠、完整雌性大鼠、去卵巢大鼠和去卵巢大鼠进行大脑中动脉阻断，22小时后测定Bcl-2 mRNA和蛋白的表达水平和定位。缺血后bcl-2 mRNA和蛋白水平仅在梗死周围区域的神经元中升高。与雄性和雌激素缺乏的雌性阉割鼠相比，完整的雌性和雌激素处理的阉割鼠显示出bcl-2 mRNA和蛋白表达的增加，并伴有梗死面积的减小。为了验证雌激素通过Bcl-2发挥神经保护作用的假设，我们比较了雄性、雌性和去卵巢的野生型小鼠和只在神经元中过表达Bcl-2的小鼠的缺血结果。野生型雌性小鼠比雄性小鼠持续更小的梗死。Bcl-2过表达减少了男性的梗死面积，但在女性中没有提供额外的保护。此外，卵巢切除术加重了野生型女性的梗死，但对Bcl-2过表达者没有影响。这些数据表明，Bcl-2的过表达模拟了内源性雌性类固醇对缺血性损伤的保护作用。我们得出结论，雌激素通过增加梗死周围区域Bcl-2的水平来拯救局灶性脑缺血后的神经元，雌激素诱导的Bcl-2基因表达是女性脑卒中神经元保护的重要下游组成部分。
Female rodents producing endogenous estrogens are protected from stroke damage in comparison with male counterparts. This natural protection is lost after ovariectomy or reproductive senescence. The aim of this study is to determine whether estrogen reduces early neuronal injury and cell loss after ischemia by increasing the expression of Bcl-2. Male, intact female, ovariectomized, and estrogen-repleted ovariectomized rats were subjected to middle cerebral artery occlusion, and 22 hr later the level and localization of Bcl-2 mRNA and protein were determined. The levels of post-ischemic bcl-2 mRNA and protein were increased exclusively in neurons within the peri-infarct region. Intact females and estrogen-treated castrates demonstrated increased bcl-2 mRNA and protein expression compared with males and estrogen-deficient females, accompanied by a decrease in infarct size. To test the hypothesis that the neuroprotective mechanism of estrogen functions via Bcl-2, we compared ischemic outcome in male, female, and ovariectomized wild-type mice and mice overexpressing Bcl-2 exclusively in neurons. Wild-type female mice sustained smaller infarcts compared with males. Bcl-2 overexpression reduced infarct size in males, but provided no added protection in the female. Moreover, ovariectomy exacerbated infarction in wildtype females, but had no effect in Bcl-2 overexpressors. These data indicate that overexpression of Bcl-2 simulates the protection against ischemic injury conferred by endogenous female sex steroids. We concluded that estrogen rescues neurons after focal cerebral ischemia by increasing the level of Bcl-2 in peri-infarct regions and that estrogen-induced bcl-2 gene expression is an important downstream component of neuronal protection in female stroke.