Hemodynamic forces 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（BMP）和TNF（. TNF α和BMP 2/4是诱导内皮活化和促进单核细胞粘附的促炎细胞因子。尽管BMP 2/4和TNF α在冠状动脉中具有重要的病理生理学意义，但调节这些细胞因子表达的机制仍完全未知。我发现，在主动脉结扎大鼠中，暴露于高压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，而暴露于正常压力的相同动物的动脉（位于缩窄下游）表现出正常的O2。生产和表型。在培养的内皮细胞中，氧化应激和振荡剪切应力被证明可以增强BMP的转录。基于这些观察和广泛的初步结果，我认为冠状动脉BMP和TNF α的表达受动脉粥样硬化倾向的血液动力学力量的调节。该项目的总体目标是检验以下假设：动脉粥样硬化倾向的血液动力学力增加ROS生成，激活冠状动脉内皮和/或平滑肌细胞中的氧化还原敏感性转录因子，从而上调BMP和TNF（诱导内皮激活，上调细胞粘附分子并增强单核细胞与内皮的粘附）。为了研究不同压力和剪切应力条件的影响并剖析潜在的分子机制，将使用体内模型（主动脉缩窄诱导的冠状动脉高血压）和新型血管培养系统。目的#1：确定动脉粥样硬化倾向的血液动力学力量是否调节BMP和TNF（在冠状动脉中）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-水平升高之间的联系，H2 O2和/或ONOO-以及内皮细胞和平滑肌细胞中促炎细胞因子的表达。目标3：为了确定动脉粥样硬化倾向的血流动力学是否激活冠状动脉中的NF-β 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：阐明骨形态发生蛋白诱导内皮活化促进冠状动脉中单核细胞粘附的机制。这些新的细胞和分子机制参与冠状动脉的早期致动脉粥样硬化的变化的鉴定可能最终导致特定的治疗干预，防止CAD的发展。

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.