Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-beta1-dependent pathway.
Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-beta1-dependent pathway.
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DOI：
10.1161/atvbaha.108.176347
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发表时间：
2009-02
期刊：
影响因子：
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通讯作者：
Yoganathan AP
中科院分区：
文献类型：
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作者：
Sucosky P;Balachandran K;Elhammali A;Jo H;Yoganathan AP
血流动力学与主动脉瓣（AV）炎症相关，但其潜在机制尚不清楚。在此，我们检验了以下假设：改变的剪切应力条件通过骨形态发生蛋白（BMP）和转化生长因子（TGF）-β1依赖性途径刺激AV瓣叶中细胞因子和粘附分子的表达。将猪AV瓣叶的心室或主动脉表面体外暴露于单向脉动和双向振荡剪切应力48小时。免疫组化法检测VCAM-1、ICAM-1、BMP-4、TGF-β1 4种炎症标志物的表达。主动脉表面暴露于脉动剪切应力（血流动力学改变），而不是振荡剪切应力，增加炎症标志物的表达。与此相反，无论是脉动或振荡剪切应力的影响表达的炎性标志物上的脑室表面。BMP抑制剂noggin显著降低了VCAM-1、ICAM-1和BMP-4的剪切应力依赖性表达，但未降低TGF-β1的表达，而TGF-β1抑制剂SB 431542阻断了暴露于脉动剪切应力的主动脉表面上的BMP-4表达。结果表明，血流动力学的改变以TGF-β1和BMP-4依赖的方式刺激AV瓣叶内皮粘附分子的表达，为AV疾病的未来药物治疗提供了一些潜在的方向。
Hemodynamics has been associated with aortic valve (AV) inflammation, but the underlying mechanisms are not well understood. Here we tested the hypothesis that altered shear stress conditions stimulate the expression of cytokines and adhesion molecules in AV leaflets via a bone morphogenic protein (BMP)-and transforming growth fact (TGF)-β1-dependent pathway. The ventricularis or aortic surface of porcine AV leaflets were exposed for 48 hours to unidirectional pulsatile and bidirectional oscillatory shear stresses ex vivo. Immunohistochemistry was performed to detect expressions of the 4 inflammatory markers VCAM-1, ICAM-1, BMP-4, and TGF-β1. Exposure of the aortic surface to pulsatile shear stress (altered hemodynamics), but not oscillatory shear stress, increased expression of the inflammatory markers. In contrast, neither pulsatile nor oscillatory shear stress affected expression of the inflammatory markers on the ventricularis surface. The shear stress—dependent expression of VCAM-1, ICAM-1, and BMP-4, but not TGF-β1, was significantly reduced by the BMP inhibitor noggin, whereas the TGF-β1 inhibitor SB431542 blocked BMP-4 expression on the aortic surface exposed to pulsatile shear stress. The results demonstrate that altered hemodynamics stimulates the expression of AV leaflet endothelial adhesion molecules in a TGF-β1-and BMP-4—dependent manner, providing some potential directions for future drug-based therapies for AV diseases.