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(BMPs)和TNFct的表达。TNFct和BMP2/4是促炎因子 诱导内皮细胞活化和促进单核细胞黏附的细胞因子。尽管 骨形态发生蛋白2/4和肿瘤坏死因子α的病理生理意义及其调控机制 冠状动脉中的这些细胞因子是完全未知的。我发现在主动脉结扎的大鼠冠状动脉中 暴露在高压下的动脉和前肢动脉表现出更高的氧化应激和 促炎症细胞因子的上调，而动脉(位于 相同动物在常压下的收缩)表现出正常的O2“产生和 表型。在培养的内皮细胞中，氧化应激和振荡切应力被显示为增强 骨形成蛋白的转录。基于这些观察和广泛的初步结果，我建议 冠状动脉BMP和TNFa的表达受易发生动脉粥样硬化的血流动力学因素的调节。这个 拟议项目的总体目标是检验以下假设：易发生动脉粥样硬化的血液动力学力量 增加内皮细胞和/或血管内皮细胞ROS生成并激活氧化还原敏感转录因子 冠脉平滑肌细胞，BMPs和TNFa表达上调， 诱导内皮细胞活化，上调细胞黏附分子，增强单核细胞 黏附于血管内皮细胞。研究不同压力和剪应力条件下的影响 并剖析了其潜在的分子机制，包括体内模型(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。目标1：确定 易发生动脉粥样硬化的血流动力学因素是否调节冠状动脉中BMPs和TNFa的表达。 目的#2：阐明动脉粥样硬化的血流动力、O2“、H_2O_2水平升高之间的联系 和/或ONOO“和促炎症细胞因子在血管内皮细胞和平滑肌细胞中的表达。 #3：确定易于动脉粥样硬化的血流动力学力量是否激活了核因子-KB、AP-1和/或PARs 以及这些转录因子是否调节BMPs和TNFa的表达。目标#4： 骨形态发生蛋白诱导内皮细胞活化促进单核细胞黏附的机制 冠状动脉。早期参与的这些新的细胞和分子机制的鉴定 冠状动脉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.