Sudar Emina, Velebit Jelena, Gluvic Zoran, Zakula Zorica, Lazic Emilija, Vuksanovic-Topic Ljiljana, Putnikovic Biljana, Neskovic Aleksandar, Isenovic Esma R
Laboratory for Molecular Genetics and Radiobiology, Institute Vinca, P.O. Box 522, 11001 Belgrade, Serbia.
J Theor Biol. 2008 Apr 21;251(4):584-92. doi: 10.1016/j.jtbi.2007.12.023. Epub 2008 Jan 17.
Causal relationship between sodium and hypertension has been proposed and various changes in Na+,K+-ATPase (sodium pump) activity have been described in established primary hypertension. A number of direct vascular effects of estradiol have been reported, including its impact on the regulation of sodium pump activity and vasomotor tone. The effects of estradiol involve the activation of multiple signaling cascades, including phosphatydil inositol-3 kinase (PI3K) and p42/44 mitogen-activated protein kinase (p42/44(MAPK)). In addition, some of the effects of estradiol have been linked to activity of cytosolic phospholipase A(2) (cPLA(2)). One possible cardioprotective mechanism of estradiol involves of the interaction between estradiol and the rennin-angiotensin system (RAS). Elevated circulating and tissue levels of angiotensin II (Ang II) have been implicated in the development of hypertension and heart failure. The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump, in vascular smooth muscle cells (VSMC). The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump activity/expression in VSMC, with particular emphasis on PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. Our primary hypothesis is that estradiol stimulates sodium pump activity/expression in VSMC via PI3K/cPLA(2)/p42/44(MAPK) dependent mechanism and, that impaired estradiol-stimulated sodium pump activity/expression in hypertensive rodent models (i.e. SHR), Ang II-mediated vascular impairment of estradiol is related to a decrease ability of estradiol to stimulate the PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. An important corollary to this hypothesis is that in hypertensive state (i.e. SHR rats) the decreasing in ACE enzyme activity and/or AT1 receptor expression caused by administration of estradiol is accompanying with abrogated ability of Ang II to decrease IRS-1/PI3K association, and consequent PI3K/cPLA(2)/p42/44(MAPK) activity and associated sodium pump activity/expression. A clear characterization of how Ang II attenuates estradiol signaling may lead to a better understanding of the molecular mechanism(s) underlying pathophysiological conditions such as hypertension and to understanding how certain pathophysiological situations affect sodium pump activity/expression in VSMC.
钠与高血压之间的因果关系已被提出，并且在已确诊的原发性高血压中已描述了钠钾ATP酶（钠泵）活性的各种变化。已报道了雌二醇的许多直接血管效应，包括其对钠泵活性调节和血管舒缩张力的影响。雌二醇的作用涉及多种信号级联的激活，包括磷脂酰肌醇-3激酶（PI3K）和p42/44丝裂原活化蛋白激酶（p42/44（MAPK））。此外，雌二醇的一些作用与胞质磷脂酶A2（cPLA2）的活性有关。雌二醇的一种可能的心脏保护机制涉及雌二醇与肾素-血管紧张素系统（RAS）之间的相互作用。循环和组织中血管紧张素II（Ang II）水平升高与高血压和心力衰竭的发生有关。我们研究的目的是阐明雌二醇和Ang II在介导血管平滑肌细胞（VSMC）中钠泵时所采用的信号机制。我们研究的目的是阐明雌二醇和Ang II在介导VSMC中钠泵活性/表达时所采用的信号机制，特别强调PI3K/cPLA2/p42/44（MAPK）信号通路。我们的主要假设是，雌二醇通过PI3K/cPLA2/p42/44（MAPK）依赖性机制刺激VSMC中的钠泵活性/表达，并且在高血压啮齿动物模型（即SHR）中，雌二醇刺激的钠泵活性/表达受损，Ang II介导的雌二醇血管损伤与雌二醇刺激PI3K/cPLA2/p42/44（MAPK）信号通路的能力降低有关。该假设的一个重要推论是，在高血压状态（即SHR大鼠）下，雌二醇给药引起的ACE酶活性和/或AT1受体表达的降低伴随着Ang II降低IRS-1/PI3K结合以及随之而来的PI3K/cPLA2/p42/44（MAPK）活性和相关钠泵活性/表达的能力丧失。清楚地了解Ang II如何减弱雌二醇信号传导可能有助于更好地理解诸如高血压等病理生理状况背后的分子机制，以及了解某些病理生理情况如何影响VSMC中的钠泵活性/表达。
