Hemodynamic forces regulate BMPs in coronary arteries

血流动力学力调节冠状动脉中的 BMP

基本信息

批准号：
7367970
负责人：
ZOLTAN Istvan UNGVARI
金额：
$ 34.66万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-15 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7367970
关键词：
Adhesions Angiotensin II Animals Arteries Arts Biology Blood Vessels Cell Adhesion Cell Adhesion Molecules Clinical Complex Condition Constriction procedure Coronary Coronary Arteriosclerosis Coronary artery Coupled Cultured Cells Data Development Dilator Disease Endothelial Cells Endothelium Environment Exhibits Figs - dietary Forelimb Functional disorder Funding Gene Expression Gene Expression Regulation Generations Genetic Transcription Goals Human Hydrogen Peroxide Hyperhomocysteinemia Hypertension In Vitro Inflammatory Lead Link Measures Mediator of activation protein Methods Modeling Molecular Molecular Biology Techniques Myocardial Organ Culture Techniques Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Pathway Analysis Personal Satisfaction Phenotype Play Poly(ADP-ribose) Polymerases Principal Investigator Production Range Rattus Reactive Oxygen Species Recombinants Reporting Research Research Personnel Resource Sharing Risk Factors Role Scheme Signal Pathway Smooth Muscle Myocytes Stress System Testing Therapeutic Therapeutic Intervention Thinking Transcription Factor AP-1 Transcriptional Activation Transcriptional Regulation Up-Regulation Vascular blood supply atherogenesis base bone morphogenic protein cell type cytokine expectation hemodynamics in vivo in vivo Model innovation monocyte normotensive novel novel diagnostics pressure prevent programs protein expression research study shear stress transcription factor

项目摘要

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.

最近的研究表明，冠状动脉疾病（CAD）的发展与增强骨形态发生蛋白（BMP）和TNFCT的表达。 TNFCT和BMP2/4是促炎性的诱导内皮激活并促进单核细胞粘附的细胞因子。尽管有 BMP2/4和TNFA的病理生理重要性，调节表达的机制冠状动脉中的这些细胞因子是完全未知的。我发现在主动脉带状的大鼠冠状动脉中暴露于高压的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，而动脉（位于下游暴露于正常压力的相同动物的缩合表现出正常的O2”产生和表型。在培养的内皮细胞中 BMP的转录。根据这些观察和广泛的初步结果冠状动脉BMP和TNFA表达受动脉粥样硬化的血液动力学调节。这拟议项目的总体目标是检验以下假设，即动脉粥样硬化的血液动力学增加ROS的产生并激活内皮和/或内皮中对氧化还原敏感的转录因子冠状动脉的平滑肌细胞，随之而来的BMP和TNFA的上调诱导内皮激活，上调的细胞粘附分子并增强单核细胞对内皮的粘附。研究不同压力和剪切应力条件的影响并剖析基本分子机制既是体内模型（主动脉收缩诱导）将使用冠状动脉高血压）和新型的血管培养系统。目标＃1：确定动脉症易血动力作用是否调节冠状动脉中BMP和TNFA的表达。目的＃2：阐明易动动式血液动力学之间的联系，O2的水平升高，H2O2 和/或onoo”以及内皮和平滑肌细胞中促炎细胞因子的表达。＃3：确定动脉粥样硬化的血液动力学是否激活NF-KB，AP-1和/或PARS 冠状动脉以及这些转录因子是否调节BMP和TNFA的表达。 AIM＃4：阐明BMP引起内皮激活促进单核细胞粘附的机制冠状动脉。鉴定这些新型细胞和分子机制冠状动脉的亲震源改变最终可能导致特定的治疗干预措施防止CAD的发展。