Zou Min-Xu, Roy Anju A, Zhao Qingshi, Kirshenbaum Lorrie A, Karmazyn Morris, Chidiac Peter
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A 5C1.
Cell Signal. 2006 Oct;18(10):1655-63. doi: 10.1016/j.cellsig.2006.01.012. Epub 2006 Mar 6.
Regulator of G protein signaling (RGS) proteins counter the effects of G protein-coupled receptors (GPCRs) by limiting the abilities of G proteins to propagate signals, although little is known concerning their role in cardiac pathophysiology. We investigated the potential role of RGS proteins on alpha1-adrenergic receptor signals associated with hypertrophy in primary cultures of neonatal rat cardiomyocytes. Levels of mRNA encoding RGS proteins 1-5 were examined, and the alpha1-adrenergic agonist phenylephrine (PE) significantly increased RGS2 gene expression but had little or no effect on the others. The greatest changes in RGS2 mRNA occurred within the first hour of agonist addition. We next investigated the effects of RGS2 overexpression produced by infecting cells with an adenovirus encoding RGS2-cDNA on cardiomyocyte responses to PE. As expected, PE increased cardiomyocyte size and also significantly upregulated alpha-skeletal actin and ANP expression, the markers of hypertrophy, as well as the Na-H exchanger 1 isoform. These effects were blocked in cells infected with the adenovirus expressing RGS2. We also examined hypertrophy-associated MAP kinase pathways, and RGS2 overexpression completely prevented the activation of ERK by PE. In contrast, the activation of both JNK and p38 unexpectedly were increased by RGS2, although the ability of PE to further activate the p38 pathway was reduced. These results indicate that RGS2 is an important negative-regulatory factor in cardiac hypertrophy produced by alpha1-adrenergic receptor stimulation through complex mechanisms involving the modulation of mitogen-activated protein kinase signaling pathways.
G蛋白信号调节蛋白（RGS）通过限制G蛋白传递信号的能力来对抗G蛋白偶联受体（GPCR）的作用，尽管人们对其在心脏病理生理学中的作用知之甚少。我们研究了RGS蛋白在新生大鼠心肌细胞原代培养中与肥大相关的α1-肾上腺素能受体信号传导中的潜在作用。检测了编码RGS蛋白1-5的mRNA水平，α1-肾上腺素能激动剂去氧肾上腺素（PE）显著增加了RGS2基因的表达，但对其他基因影响很小或没有影响。RGS2 mRNA的最大变化发生在添加激动剂后的第一小时内。接下来，我们研究了用编码RGS2-cDNA的腺病毒感染细胞产生的RGS2过表达对心肌细胞对PE反应的影响。正如预期的那样，PE增加了心肌细胞大小，并显著上调了肥大标志物α-骨骼肌肌动蛋白和心钠素（ANP）的表达以及钠-氢交换体1亚型。这些作用在感染表达RGS2的腺病毒的细胞中被阻断。我们还研究了与肥大相关的丝裂原活化蛋白激酶途径，RGS2过表达完全阻止了PE对细胞外信号调节激酶（ERK）的激活。相反，RGS2意外地增加了应激活化蛋白激酶（JNK）和p38的激活，尽管PE进一步激活p38途径的能力降低了。这些结果表明，RGS2是α1-肾上腺素能受体刺激通过涉及丝裂原活化蛋白激酶信号通路调节的复杂机制产生心脏肥大的重要负调节因子。
