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首页> 外文期刊>Cellular Signalling >Enhanced levels of endogenous endothelin-1 contribute to the over expression of Giα protein in vascular smooth muscle cells from SHR: Role of growth factor receptor activation
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Enhanced levels of endogenous endothelin-1 contribute to the over expression of Giα protein in vascular smooth muscle cells from SHR: Role of growth factor receptor activation

机译：内源性内皮素-1水平升高导致SHR血管平滑肌细胞中Giα蛋白的过度表达：生长因子受体激活的作用

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摘要

We earlier showed that vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit increased expression of Gi proteins. Since the levels of endothelin-1 (ET-1) are enhanced in VSMC from SHR, we undertook the present study to examine the implication of endogenous ET-1 and the underlying mechanisms in the enhanced expression of Giα proteins in VSMC from SHR. The enhanced expression of Giα-2 and Giα-3 proteins in VSMC from SHR was inhibited by ET_A and ET_B receptor antagonists, BQ123 and BQ788 respectively. In addition, these antagonists also attenuated the enhanced inhibition of forskolin-stimulated adenylyl cyclase activity by low concentrations of GTPγS and by inhibitory hormones in VSMC from SHR compared to WKY. Furthermore, AG1295, AG1024 and PP2, inhibitors of platelet derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF-1R) and c-Src respectively, inhibited the enhanced expression of Giα protein and the enhanced phosphorylation of PDGFR and IGF-1R in VSMC from SHR to WKY levels. In addition, NAD(P)H oxidase inhibitor DPI and N-acetylcysteine (NAC), a scavenger of superoxide anion (O_2~-) also inhibited the enhanced phosphorylation of PDGFR and IGF-1R and c-Src in VSMC from SHR to control levels. Furthermore, the augmented phosphorylation of ERK1/2 in VSMC from SHR was attenuated by BQ123 and BQ788, growth factor receptors inhibitors and PP2. These results suggest that the enhanced levels of endogenous ET-1 in VSMC from SHR increase oxidative stress, which through c-Src-mediated activation of growth factor receptors and associated MAP kinase signaling, contribute to the enhanced expression of Giα proteins.
机译：我们较早的研究表明，自发性高血压大鼠（SHR）的血管平滑肌细胞（VSMC）表现出增加的Gi蛋白表达。由于SHR在VSMC中内皮素1（ET-1）的水平升高，因此我们进行了本研究，以检查内源性ET-1的影响以及Gib蛋白在SHR的VSMC中增强表达的潜在机制。 ET_A和ET_B受体拮抗剂BQ123和BQ788分别抑制了SHR在VSMC中Giα-2和Giα-3蛋白的表达增强。此外，与WKY相比，这些拮抗剂还通过低浓度的GTPγS和SHR的VSMC中的抑制激素，减弱了对毛喉素刺激的腺苷酸环化酶活性的增强抑制作用。此外，血小板衍生生长因子受体（PDGFR），胰岛素样生长因子1受体（IGF-1R）和c-Src抑制剂AG1295，AG1024和PP2分别抑制了Giα蛋白的表达增强和PDGFR的磷酸化增强从SHR到WKY，VSMC中的IGF-1R和IGF-1R。此外，NAD（P）H氧化酶抑制剂DPI和超氧阴离子（O_2〜-）的清除剂N-乙酰半胱氨酸（NAC）也抑制了VSMC中PDGFR和IGF-1R和c-Src的磷酸化增强，从SHR到对照水平。此外，BQ123和BQ788，生长因子受体抑制剂和PP2减弱了SHR在VSMC中ERK1 / 2增强的磷酸化作用。这些结果表明，来自SHR的VSMC中内源性ET-1的水平升高会增加氧化应激，其通过c-Src介导的生长因子受体激活和相关的MAP激酶信号传导，有助于Giα蛋白的表达增强。

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