Hemodynamic forces regulate BMPs in coronary arteries

最近的研究表明，冠状动脉疾病（CAD）的发展与增强的 骨形态发生蛋白（BMP）和TNF α的表达。TNF α和BMP 2/4是促炎性的 诱导内皮活化和促进单核细胞粘附的细胞因子。尽管 BMP 2/4和TNF α的病理生理重要性，调节BMP 2/4和TNF α表达的机制， 冠状动脉中的这些细胞因子完全未知。我发现在主动脉结扎的大鼠中 暴露于高压的动脉和前肢动脉表现出增加的氧化应激， 促炎细胞因子的上调，而动脉（位于下游的 缩窄）表现出正常的O2-产生， 表型。在培养的内皮细胞中，氧化应激和振荡剪切应力显示出增强 BMP的转录。根据这些观察和广泛的初步结果，我建议 冠状动脉BMP和TNF α的表达受动脉粥样硬化倾向的血液动力学力的调节。的 该项目的总体目标是检验动脉粥样硬化倾向的血流动力学力 增加ROS产生并激活内皮细胞和/或 冠状动脉的平滑肌细胞，随之而来的BMP和TNF α的上调， 诱导内皮细胞活化，上调细胞粘附分子和增强单核细胞 粘附于内皮。研究不同压力和剪切应力条件下的影响 并剖析了潜在的分子机制，包括体内模型（主动脉缩窄诱导的 冠状动脉高血压）和新的血管培养系统。目标1：确定 动脉粥样硬化倾向的血流动力学是否调节冠状动脉中BMP和TNF α的表达。 目的#2：阐明易致动脉粥样硬化的血流动力学力量、O2-、H2 O2水平升高之间的联系 和/或ONOO”以及促炎细胞因子在内皮细胞和平滑肌细胞中的表达。目的 #3：为了确定动脉粥样硬化倾向的血液动力学力量是否激活NF-κ B，AP-1和/或PARS， 冠状动脉和这些转录因子是否调节BMP和TNF α的表达。目标4： 为了阐明骨形成蛋白诱导内皮细胞活化促进单核细胞粘附的机制， 冠状动脉这些新的细胞和分子机制的鉴定涉及早期 冠状动脉中的促动脉粥样硬化改变可能最终导致特定的治疗干预 阻碍了CAD的发展。

Recent studies suggest that development of coronary artery disease (CAD) is associated with an enhanced expression of bone morphogenic proteins (BMPs) and TNFct. TNFct and BMP2/4 are pro-inflammatory cytokines that induce endothelial activation and promote monocyte adhesion. Despite the pathophysiological importance of BMP2/4 and TNFa, the mechanisms that regulate the expression of these cytokines in coronary arteries are completely unknown. I found that in aortic banded rats coronary arteries and forelimb arteries which are exposed to high pressure exhibit an increased oxidative stress and an up-regulation of pro-inflammatory cytokines, whereas arteries (located downstream from the coarctation) of the same animals which are exposed to normal pressure exhibit normal O2" production and phenotype. In cultured endothelial cells oxidative stress and oscillatory shear stress was shown to enhance the transcription of BMPs. On the basis of these observations and extensive preliminary results I propose that coronary arterial BMP and TNFa expression is regulated by athero-prone hemodynamic forces. The overall goal of the proposed project is to test the hypothesis that athero-prone hemodynamic forces increase ROS generation and activate redox-sensitive transcription factors in endothelial and/or smooth muscle cells of coronary arteries with the consequent up-regulation of BMPs and TNFa, which induce endothelial activation, up-regulating cellular adhesion molecules and enhancing monocyte adhesion to the endothelium. To investigate the effects of different pressure and shear stress conditions and dissect the underlying molecular mechanisms both an in vivo model (aortic constriction-induced coronary arterial hypertension) and a novel vessel culture system will be used. Aim #1: To determine whether athero-prone hemodynamic forces regulate expression of BMPs and TNFa in coronary arteries. Aim #2: To elucidate the link between athero-prone hemodynamic forces, increased levels of O2", H2O2 and/or ONOO" and expression of pro-inflammatory cytokines in endothelial and smooth muscle cells. Aim #3: To determine whether athero-prone hemodynamic forces activate NF-KB, AP-1 and/or PARS in coronary arteries and whether these transcription factors regulate expression of BMPs and TNFa. Aim #4: To elucidate the mechanisms by which BMPs elicit endothelial activation promoting monocyte adhesion in coronary arteries. The identification of these novel cellular and molecular mechanisms involved in early pro-atherogenic alterations in coronary arteries may ultimately lead to specific therapeutic interventions preventing the development of CAD.