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雌激素的心脏保护作用-----与#beta#_(1)--肾上腺素受体的相互作用及其信号通路

黄心璇, 马妍, 郑永添, 黄德明

香港大学医学院生理学系.香港

摘要

雌激素是女性体内主要的类固醇性激素。对于心肌缺血性伤害,切除卵巢的成年雌性大鼠在#beta#--肾上腺素受体激动时,比正常雌性大鼠呈现更严重的心肌损伤;而去卵巢后的雌激素替补组大鼠对#beta#--肾上腺素受体激动时心肌缺血性伤害的反应则又回复到正常雌性大鼠水平,这为雌激素对抗缺血性伤害的心脏保护作用提供了证据。雌激素的这种保护作用是通过下调#beta#_(1)--肾上腺素受体的表达来实现的。也有研究证明,雌激素能抑制蛋白激酶A(protein kinase A,PKA)的表达和活性,PKA是G_(s)蛋白/腺苷酸环化酶(adenylyl cyclase,AC)/cAMP/PKA通路的第二信使,而该通路最终影响心肌的收缩功能。有初步证据表明雌激素还能抑制#beta#_(1)--肾上腺素受体通路下游的另一种第二信使钙调蛋白激酶II--#delta#c(Ca~(2+)/calmodulin kinase II--#delta#c,CaMKII--#delta#c)的活性,而CaMKII--#delta#c参与PKA非依赖性的细胞凋亡。即时给予生理浓度雌激素可不通过雌激素受体而直接抑制心肌#beta#_(1)--肾上腺素受体并减弱Ca~(2+)内流。此外,脑研究也显示雌激素能抑制负责调节动脉血压脑区的#beta#_(1)--肾上腺素受体活性。因此,雌激素和#beta#_(1)--肾上腺素受体之间的相互作用及其信号通路十分复杂。雌激素不仅主导性别决定,在机体其它功能例如心脏保护方面也具有重要作用。

关键词： 雌激素; #beta#_(1)-肾上腺素受体; 钙调蛋白激酶II; 蛋白激酶A; 心脏保护; 凋亡

Cardioprotection by the female sex hormone--interaction with the #beta#_(1)--adrenoceptor and its signaling pathways

Wong K A, Ma Yan, Cheng Wingtim, Wong Takming

Department of Physiology, the University of Hong Kong.Hong Kong

Abstract

Estrogen is a steroid and the predominant female sex hormone in the body. Ovariectomised (OVX) adult female rats exhibit greater myocardial injury compared to the sham rats following ischemic insult in the presence of #beta#-adrenoceptor stimulation. Estrogen replacement restores the response of OVX female rats to ischemic/#beta#-adrenoceptor stimulation to that of normal female rats, providing evidence for a cardioprotective role of estrogen during ischemic insult. The protective effect is due to down-regulation of the #beta#_(1)-adrenoceptor. There is also evidence that estrogen suppresses the expression and activity of protein kinase A (PKA), a second messenger of the G_(s) protein/adenylyl cyclase/cAMP/PKA pathway which ultimately influences contractile function. There is also preliminary evidence that estrogen may suppress the activity of Ca~(2+)/calmodulin kinase Ⅱ#delta#c isoform (CaMKII-#delta#c), another downstream second messenger of the #beta#_(1)-adrenoceptor pathway, which is involved in PKA-independent cell apoptosis. Acute administration of estrogen at physiological level could inhibit myocardial #beta#_(1)-adrenoceptor and attenuate Ca~(2+) influx independent of the estrogen receptor. In addition, brain studies also show estrogen inhibits the activities activated by the #beta#-adrenoceptor in brain regions responsible for the regulation of arterial blood pressure. Thus, it can be appreciated that the interaction between estrogen and the #beta#_(1)-adrenoceptor and its signaling pathways is a complex one. Estrogen plays an important role not only in reproduction but also in other regulatory functions such as cardioprotection.

Key words: Estrogen;#beta#_(1)-adrenoceptor;;;;

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引用本文：

黄心璇, 马妍, 郑永添, 黄德明. 雌激素的心脏保护作用-----与#beta#_(1)--肾上腺素受体的相互作用及其信号通路[J]. 生理学报 2007; 59 (5): 571-577.

Wong K A, Ma Yan, Cheng Wingtim, Wong Takming. Cardioprotection by the female sex hormone--interaction with the #beta#_(1)--adrenoceptor and its signaling pathways. Acta Physiol Sin 2007; 59 (5): 571-577 (in Chinese with English abstract).