IGF-I-induced VEGF expression in HUVEC involves phosphorylation and inhibition of poly(ADP-ribose)polymerase
IGF-I-induced VEGF expression in HUVEC involves phosphorylation and inhibition of poly(ADP-ribose)polymerase
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DOI：
10.1016/j.bbrc.2005.12.148
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发表时间：
2006-03-03
影响因子：
3.1
通讯作者：
Hussain, MZ
中科院分区：
文献类型：
--
作者：
Beckert, S;Farrahi, F;Hussain, MZ
胰岛素样生长因子-I（IGF-I）已被证明可通过增强血管内皮生长因子（VEGF）的表达来促进血管生成。然而，IGF-I如何诱导VEGF表达尚未完全了解。通过这项研究，我们提出了一个新的可能机制，涉及下调聚（ADP-核糖基）化（pADPR）。我们首先证明了IGF-I增加了内皮细胞中VEGF蛋白的表达。丝裂原活化激酶（PD 98059）、磷脂酰-3-肌醇激酶（LY 294002）和蛋白激酶C（星形孢菌素）抑制剂减弱了IGF-I的作用，表明参与了信号转导。由于pADPR和转录活性之间存在着联系，我们将重点放在聚（ADP-核糖）聚合酶（PARP）的可能作用上。通过3-氨基苯甲酰胺或烟酰胺抑制PARP增强VEGF表达。此外，IGF-I显著降低PARP活性。此外，IGF-I介导的PARP抑制可以被证明是蛋白磷酸化的结果，因为PARP的磷酸化降低了其体外活性，并且IGF-I处理内皮细胞诱导PARP磷酸化。IGF-I介导的PARP磷酸化和抑制代表了VEGF蛋白表达的新机制。(c)2005年爱思唯尔公司All rights reserved.
Insulin-like growth factor-I (IGF-I) has been shown to promote angiogenesis by enhancing vascular endothelial growth factor (VEGF) expression. However, how IGF-I-induces VEGF expression is not yet fully understood. With this investigation, we propose a new possible mechanism involving downregulation of poly(ADP-ribosyl)ation (pADPR). We first demonstrated that IGF-I increased VEGF protein expression in endothelial cells. Inhibitors of mitogen activated kinase (PD 98059), phosphatidyl-3-inositol-kinase (LY 294002), and protein kinase C (staurosporine) diminished the IGF-I effect suggesting the involvement of signal transduction. Since there is an established link between pADPR and transcriptional activity, we focused oil a possible role of poly(ADP-ribose)polymerase (PARP). The inhibition of PARP by 3-aminobenzamide or nicotinamide enhanced VEGF expression. Additionally, IGF-I markedly decreased PARP activity. Furthermore, the IGF-I-mediated inhibition of PARP could be demonstrated as a result of protein phosphorylation since phosphorylation of PARP decreased its activity in vitro and IGF-I treatment of endothelial cells induced PARP phosphorylation. The IGF-I-mediated phosphorylation and inhibition of PARP represent a novel mechanism of VEGF protein expression. (c) 2005 Elsevier Inc. All rights reserved.