Hemodynamic Forces Up-regulate BMPs in Coronary Arteries

描述（由申请人提供）：最近的研究表明，冠状动脉疾病（CAD）的发展与骨形态发生蛋白（BMPs）和肿瘤坏死因子（TNF）的表达增强有关。TNF(和BMP2/4是促炎细胞因子，可诱导内皮细胞活化并促进单核细胞粘附。尽管BMP2/4和TNF在病理生理上具有重要意义，但在冠状动脉中调节这些细胞因子表达的机制是完全未知的。我发现，在主动脉束带的大鼠中，暴露在高压下的冠状动脉和前肢动脉表现出增加的氧化应激和促炎细胞因子的上调，而同一动物暴露在正常压力下的动脉（位于缩窄下游）表现出正常的氧气。-生产和表型。在培养的内皮细胞中，氧化应激和振荡剪切应激可增强bmp的转录。在这些观察和广泛的初步结果的基础上，我提出冠状动脉BMP和TNF的表达是由动脉粥样硬化倾向的血流动力学力调节的。本项目的总体目标是验证这样一种假设，即易致动脉粥样硬化的血流动力学力增加了冠状动脉内皮细胞和/或平滑肌细胞中ROS的产生，并激活氧化还原敏感转录因子，从而导致bmp和TNF的上调，从而诱导内皮活化，上调细胞粘附分子，增强单核细胞对内皮的粘附。为了研究不同压力和剪切应力条件的影响，并解剖潜在的分子机制，我们将使用体内模型（主动脉收缩诱导的冠状动脉高血压）和一种新的血管培养系统。目的1：确定动脉粥样硬化倾向的血流动力学力是否调节冠状动脉中bmp和TNF的表达。目的2：阐明易致动脉粥样硬化的血流动力学力与血氧水平升高之间的联系。-， H2O2和/或ONOO-和促炎细胞因子在内皮和平滑肌细胞中的表达。目的3：确定易发生动脉粥样硬化的血流动力学力是否激活冠状动脉中的NF-(B)、AP-1和/或PARS，以及这些转录因子是否调节bmp和TNF的表达。目的4：阐明bmp诱导内皮细胞活化促进冠状动脉单核细胞粘附的机制。这些涉及冠状动脉早期促动脉粥样硬化改变的新细胞和分子机制的鉴定可能最终导致预防冠心病发展的特异性治疗干预。

DESCRIPTION (provided by applicant): Recent studies suggest that development of coronary artery disease (CAD) is associated with an enhanced expression of bone morphogenic proteins (BMPs) and TNF(. TNF( and BMP2/4 are pro-inflammatory cytokines that induce endothelial activation and promote monocyte adhesion. Despite the pathophysiological importance of BMP2/4 and TNF(, 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 were shown to enhance the transcription of BMPs. On the basis of these observations and extensive preliminary results I propose that coronary arterial BMP and TNF( 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 TNF(, 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 TNF( 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-(B, AP-1 and/or PARS in coronary arteries and whether these transcription factors regulate expression of BMPs and TNF(. 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.