Regulation of bone morphogenetic protein-2 expression in endothelial cells -: Role of nuclear factor-κB activation by tumor necrosis factor-α, H2O2, and high intravascular pressure
Regulation of bone morphogenetic protein-2 expression in endothelial cells -: Role of nuclear factor-κB activation by tumor necrosis factor-α, H2O2, and high intravascular pressure
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DOI：
10.1161/01.cir.0000164201.40634.1d
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发表时间：
2005-05-10
期刊：
影响因子：
37.8
通讯作者：
Ungvari, Z
中科院分区：
文献类型：
--
作者：
Csiszar, A;Smith, KE;Ungvari, Z
骨形态发生蛋白-2（BMP-2）是一种转化生长因子β超家族成员细胞因子，在血管发育和病理生理过程中起重要作用，包括内皮细胞活化，内皮细胞活化可能导致冠状动脉粥样硬化的发生，但BMP-2在动脉中表达的调控因子尚不清楚。我们检验了内皮细胞中BMP-2的表达受H2 O2和核因子（NF）-κ B依赖性途径控制的假设，该途径可被促炎和机械刺激激活。2 NF-κ B B抑制剂（吡咯烷二硫代氨基甲酸酯和SN-50）、p65沉默（siRNA）或过氧化氢酶抑制的原代冠状动脉内皮细胞和人脐静脉内皮细胞中的mRNA和蛋白。H2 O2的给药也引起NF-κ B B活化和BMP-2诱导。在器官培养中，大鼠动脉暴露于高压（160 mm Hg）引起H2 O2产生，NF-κ B B核转位和BMP-2表达上调。虽然高压上调TNF-α，它似乎直接调节BMP-2的表达，因为BMP-2的上调也观察到在血管中的TNF-α敲除mice. Conclusions血管BMP- 2的表达可以调节H2 O2介导的活化NF-κ B B的炎症刺激和高血管内压。
Background-Recent studies suggest that bone morphogenetic protein-2 (BMP-2), a transforming growth factor-beta superfamily member cytokine, plays an important role both in vascular development and pathophysiological processes, including endothelial activation that is likely to contribute to the development of coronary atherosclerosis, yet the factors that regulate arterial expression of BMP-2 are completely unknown. We tested the hypothesis that BMP-2 expression in endothelial cells is governed by an H2O2 and nuclear factor (NF)-kappa B-dependent pathway that can be activated by both proinflammatory and mechanical stimuli.Methods and Results-The proinflammatory cytokine tumor necrosis factor (TNF)-alpha induced NF-kappa B activation and elicited significant increases in BMP-2 mRNA and protein in primary coronary arterial endothelial cells and human umbilical vein endothelial cells that were prevented by NF-kappa B inhibitors (pyrrolidine dithiocarbamate and SN-50), silencing of p65 (siRNA), or catalase. Administration of H2O2 also elicited NF-kappa B activation and BMP-2 induction. In organ culture, exposure of rat arteries to high pressure (160 mm Hg) elicited H2O2 production, nuclear translocation of NF-kappa B, and upregulation of BMP-2 expression. Although high pressure upregulated TNF-alpha, it appears that it directly regulates BMP-2 expression, because upregulation of BMP-2 was also observed in vessels of TNF-alpha knockout mice.Conclusions-Vascular BMP- 2 expression can be regulated by H2O2-mediated activation of NF-kappa B both by inflammatory stimuli and by high intravascular pressure.