Ca2+-dependent mitogen-activated protein kinase activation in spontaneously hypertensive rat vascular smooth muscle defines a hypertensive signal transduction phenotype
Ca2+-dependent mitogen-activated protein kinase activation in spontaneously hypertensive rat vascular smooth muscle defines a hypertensive signal transduction phenotype
复制标题
DOI：
10.1161/01.res.78.6.962
复制
发表时间：
1996-06-01
影响因子：
20.1
通讯作者：
Berk, BC
中科院分区：
文献类型：
--
作者：
Lucchesi, PA;Bell, JM;Berk, BC
高血压患者血管平滑肌细胞（VSMC）功能改变的机制尚不清楚。在遗传性高血压的自发性高血压大鼠（SHR）模型中，VSMC功能存在多种异常，包括生长增加、Na+-H+交换增加和蛋白激酶C信号转导增加。有丝分裂原活化蛋白激酶（mitogen-activated protein kinases，MAP）是近年来发现的一类重要的生长因子信号转导调节因子。在本研究中，MAP激酶功能的高血压表型的改变进行了研究，使用血管紧张素II（Ang II，100 nmol/L）或血小板衍生生长因子-BB（PDGF-BB，10 ng/mL）刺激的早期传代SHR和Wistar-Kyoto（WKY）VSMCs。MAP激酶活性通过凝胶内激酶测定和Western印迹分析来测量。SHR和WKY大鼠血管紧张素Ⅱ介导的MAP激酶激活存在两个差异：（1）SHR血管紧张素Ⅱ刺激后MAP激酶失活较WKY快; (2)在SHR VSMCs的活动表现出更大的依赖于Ca 2+动员，因为螯合的细胞内Ca 2+与BAPTA抑制最大活动的95%，SHR VSMCs，但只有50%，在WKY VSMCs。与Ang II的结果相反，没有观察到PDGF刺激的MAP激酶活性的差异。这些研究结果建立了MAP激酶的激活血管紧张素II作为一个功能，区分SHR VSMCs从WKY VSMCs，并表明，MAP激酶信号调节的差异可能会改变细胞的事件，增加SHR高血压的遗传模型。
The mechanisms responsible for altered vascular smooth muscle cell (VSMC) function in hypertension remain unknown. In the spontaneously hypertensive rat (SHR) model of genetic hypertension, there are multiple abnormalities in VSMC function, including increased growth, Na+-H+ exchange, and increased signal transduction by protein kinase C. The family of kinases termed mitogen-activated protein (MAP) kinases has recently been shown to be essential mediators of growth factor signal transduction. In the present study, alterations in MAP kinase function in the hypertensive phenotype were investigated using early-passage SHR and Wistar-Kyoto (WKY) VSMCs stimulated with angiotensin II (Ang II, 100 nmol/L) or platelet-derived growth factor-BB (PDGF-BB, 10 ng/mL). MAP kinase activity was measured by in-gel kinase assays and Western blot analysis. Two differences between SHR and WKY rats were observed for Ang II-mediated MAP kinase activation: (1) Inactivation after Ang II stimulation was more rapid in SHR than WKY VSMCs. (2) Activity in SHR VSMCs showed a greater dependence on Ca2+ mobilization, since chelation of intracellular Ca2+ with BAPTA inhibited maximal activity by 95% in SHR VSMCs but by only 50% in WKY VSMCs. In contrast to the results with Ang II, no differences in PDGF-stimulated MAP kinase activity were observed. These findings establish activation of MAP kinase by Ang II as a feature that distinguishes SHR VSMCs from WKY VSMCs and suggest that differences in regulation of MAP kinase signaling may alter cellular events that are increased in the SHR genetic model of hypertension.