Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase
Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase
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DOI：
10.1161/01.res.0000145728.22878.45
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发表时间：
2004-10-15
影响因子：
20.1
通讯作者：
Jo, H
中科院分区：
文献类型：
--
作者：
Sorescu, GP;Song, H;Jo, H
动脉粥样硬化是一种炎性疾病，优先发生在动脉区域，暴露于扰动的流动条件，包括振荡剪切应力（OS）。OS暴露诱导骨形态发生蛋白4（BMP 4）的内皮表达，这反过来又可能激活细胞间粘附分子-1（ICAM-1）的表达和单核细胞粘附。还已知OS通过从还原的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶产生活性氧物质（ROS）来诱导单核细胞粘附，从而提高了BMP 4可能通过ROS依赖性机制刺激炎症反应的可能性。在这里，我们表明，活性氧清除剂阻断ICAM-1的表达和单核细胞粘附诱导的BMP 4或OS在内皮细胞（EC）。与OS类似，BMP 4刺激EC产生（HO 2）-O-2和O-2（-）。接下来，我们使用从p47 phox（-/-）小鼠（MAE-p47（-/-））获得的EC，其不响应OS产生ROS，以确定NADPH氧化酶的作用。与OS相似，BMP 4不能诱导MAE-p47（-/-）细胞与单核细胞的粘附，但当转染p47（phox）质粒后，粘附恢复。此外，OS诱导的O-2（-）产生被noggin（一种BMP拮抗剂）阻断，表明BMP的作用。此外，OS增加gp 91 phox（nox 2）和nox 1 mRNA水平，而降低nox 4。相反，BMP 4诱导nox 1 mRNA表达，而nox 2和nox 4分别减少或不受影响。此外，OS诱导的单核细胞粘附被阻断敲低nox 1与小干扰RNA（siRNA）。最后，BMP 4 siRNA抑制OS诱导的ROS产生和单核细胞粘附。总之，这些结果表明，由OS在EC中产生的BMP 4刺激ROS从nox 1依赖性NADPH氧化酶释放，导致炎症，这是一个关键的早期致动脉粥样硬化步骤。
Atherosclerosis is an inflammatory disease occurring preferentially in arterial regions exposed to disturbed flow conditions including oscillatory shear stress (OS). OS exposure induces endothelial expression of bone morphogenic protein 4 (BMP4), which in turn may activate intercellular adhesion molecule-1 (ICAM-1) expression and monocyte adhesion. OS is also known to induce monocyte adhesion by producing reactive oxygen species (ROS) from reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, raising the possibility that BMP4 may stimulate the inflammatory response by ROS-dependent mechanisms. Here we show that ROS scavengers blocked ICAM-1 expression and monocyte adhesion induced by BMP4 or OS in endothelial cells (ECs). Similar to OS, BMP4 stimulated (HO2)-O-2 and O-2(-) production in ECs. Next, we used ECs obtained from p47phox(-/-) mice (MAE-p47(-/-)), which do not produce ROS in response to OS, to determine the role of NADPH oxidases. Similar to OS, BMP4 failed to induce monocyte adhesion in MAE-p47(-/-), but it was restored when the cells were transfected with p47(phox) plasmid. Moreover, OS-induced O-2(-) production was blocked by noggin (a BMP antagonist), suggesting a role for BMP. Furthermore, OS increased gp91phox (nox2) and nox1 mRNA levels while decreasing nox4. In contrast, BMP4 induced nox1 mRNA expression, whereas nox2 and nox4 were decreased or not affected, respectively. Also, OS-induced monocyte adhesion was blocked by knocking down nox1 with the small interfering RNA (siRNA). Finally, BMP4 siRNA inhibited OS-induced ROS production and monocyte adhesion. Together, these results suggest that BMP4 produced in ECs by OS stimulates ROS release from the nox1-dependent NADPH oxidase leading to inflammation, a critical early atherogenic step.