Hemodynamic forces regulate BMPs in coronary arteries

血流动力学力调节冠状动脉中的 BMP

• 批准号: 7036294
• 负责人: ZOLTAN Istvan UNGVARI
• 金额: $ 35.4万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 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/7036294
• 关键词: AP1 protein; biomechanics; bone morphogenetic proteins; coronary artery; coronary disorder; gel mobility shift assay; gene induction /repression; hemodynamics; immunofluorescence technique; inflammation; laboratory mouse; laboratory rat; nuclear factor kappa beta; organ culture; oxidative stress; peroxides; peroxynitrites; protein biosynthesis; shear stress; superoxides; transcription factor; tumor necrosis factor alpha; vascular cell adhesion molecule; vascular endothelium; vascular resistance; vascular smooth muscle

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.

描述（由申请人提供）：最近的研究表明，冠状动脉疾病（CAD）的发展与骨形态形态发生蛋白（BMP）和TNF的表达增强有关（。TNF（。TNF（和BMP2/4）（和BMP2/4）是促炎细胞因子，是诱导内皮激活和促进​​pathypyte hishesionsimoligy of Pathysipy and tnf的促疾病的细胞因子。调节这些细胞因子在冠状动脉中的表达是完全未知的。表现出培养的内皮细胞氧化应激和振荡性剪切应力，以增强BMP的转录。拟议项目的总体目标是检验以下假说：冠状动脉和/或在冠状动脉和/或平滑肌细胞中激活氧化还原敏感的转录因子的假说，并在BMP和TNF上上调冠状动脉和/或平滑肌细胞（诱导内皮激活的细胞激活，并增强了刺激性的粘附分类，它们会诱导内皮激活的上调。为了研究不同压力和剪切应力条件的影响，并阐明了基本的分子机制，即体内模型（主动脉收缩引起的冠状动脉高压），并使用新型的血管培养系统。血液动力学，O2.-，H2O2和/或ONOO-的水平升高，以及内皮和平滑肌细胞中促炎细胞因子的表达。目的＃3：确定动脉血流动力学激活NF-（B，AP-1和/或PARS中的冠状动脉动脉中是否激活了这些转录因子是否调节BMP和TNF的表达（。目的＃4：阐明BMP引起的内皮激活的机制，促进单细胞粘附的机制，这些机制涉及单细胞粘附在冠状动脉和这些核心细胞中的细胞，并识别这些核心菌株，这些机构鉴定了这些识别这些疾病的疾病，鉴定了这些疾病的疾病，鉴定了这些疾病的疾病。冠状动脉动脉的亲触觉改变可能最终导致特定的治疗干预措施，以阻止CAD的发展。