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首页> 外文期刊>American Journal of Physiology >Cytokine stimulation of pregnancy-associated plasma protein A expression in human coronary artery smooth muscle cells: inhibition by resveratrol.
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Cytokine stimulation of pregnancy-associated plasma protein A expression in human coronary artery smooth muscle cells: inhibition by resveratrol.

机译：细胞因子刺激妊娠相关血浆蛋白A在人冠状动脉平滑肌细胞中的表达：白藜芦醇的抑制作用。

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摘要

Through specific cleavage of proteins that bind and inhibit insulin-like growth factor-I (IGF-I), pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF-I availability, and, consequently, receptor activation. PAPP-A expression is increased in experimental models of vascular injury and in human atherosclerotic plaque; however, little is known about the regulation of PAPP-A gene expression in vascular cells. In this study, we tested the hypothesis that proinflammatory cytokines involved in the vascular injury response stimulate PAPP-A gene expression in human coronary artery smooth muscle cells (hCASMC) in culture. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta stimulated PAPP-A gene expression in a time- and dose-dependent manner. The effect of these cytokines appears to be at the level of transcription because actinomycin D completely prevented the induction of PAPP-A gene expression. Accumulation of PAPP-A in cell-conditioned medium paralleled mRNA synthesis, as did proteolytic activity against IGF binding protein-4 (IGFBP-4). Interestingly, pretreatment of hCASMC with resveratrol, a polyphenol found in the skin of grapes and in red wine purported to underlie the "French paradox," inhibited TNF-alpha- and IL-1beta-induced PAPP-A expression and, hence, its IGFBP-4 proteolytic activity. Resveratrol had no effect on basal PAPP-A expression and protease activity. Our finding that PAPP-A gene expression in hCASMC is stimulated by TNF-alpha and IL-1beta suggests a mechanism for the regulation of PAPP-A in response to vascular injury that may contribute to the enhanced IGF-I bioactivity in intimal hyperplasia and atherosclerotic plaque development. Our results also suggest that PAPP-A may be a target of the cardiovascular system-protective effects of resveratrol.
机译：通过结合和抑制胰岛素样生长因子-I（IGF-I）的蛋白的特异性切割，与妊娠相关的血浆蛋白-A（PAPP-A）增强了局部IGF-1的利用率，并因此增强了受体的激活作用。在血管损伤的实验模型和人的动脉粥样硬化斑块中，PAPP-A表达增加。然而，关于血管细胞中PAPP-A基因表达的调控知之甚少。在这项研究中，我们测试了以下假设：参与血管损伤反应的促炎细胞因子刺激培养的人冠状动脉平滑肌细胞（hCASMC）中的PAPP-A基因表达。肿瘤坏死因子（TNF）-α和白介素（IL）-1β以时间和剂量依赖性方式刺激PAPP-A基因表达。这些细胞因子的作用似乎在转录水平，因为放线菌素D完全阻止了PAPP-A基因表达的诱导。 PAPP-A在细胞条件培养基中的积累与mRNA合成平行，对IGF结合蛋白4（IGFBP-4）的蛋白水解活性也是如此。有趣的是，用白藜芦醇对hCASMC进行预处理，白藜芦醇是一种在葡萄皮和红酒中发现的多酚，据称是“法国悖论”的基础，可抑制TNF-α和IL-1β诱导的PAPP-A表达，因此抑制了其IGFBP。 -4蛋白水解活性。白藜芦醇对基础PAPP-A表达和蛋白酶活性没有影响。我们的发现发现hCASMC中PAPP-A基因的表达受到TNF-α和IL-1beta的刺激，这提示了针对血管损伤的PAPP-A调节机制，这可能有助于内膜增生和动脉粥样硬化中IGF-I生物活性的增强。斑块发展。我们的结果还表明，PAPP-A可能是白藜芦醇对心血管系统的保护作用的靶标。

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