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) 的发展与骨形态发生蛋白 (BMP) 和 TNF() 的表达增强有关。TNF( 和 BMP2/4 是促炎细胞因子，可诱导内皮细胞尽管 BMP2/4 和 TNF( 具有病理生理学重要性，但调节这些细胞因子在冠状动脉中表达的机制完全未知。我发现在主动脉带中暴露于高压的大鼠冠状动脉和前肢动脉表现出氧化应激增加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 .- 产生和表型。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。根据这些观察和广泛的​​初步结果，我建议冠状动脉 BMP 和TNF(表达受动脉粥样硬化倾向的血流动力学力调节。该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流动力学会增加 ROS 的产生并激活冠状动脉内皮细胞和/或平滑肌细胞中的氧化还原敏感转录因子，从而导致 BMP 和 TNF 的上调。 ，诱导内皮激活，上调细胞粘附分子并增强单核细胞对内皮的粘附，以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（主动脉缩窄引起的冠状动脉高压）和新型血管培养系统。目标#1：确定易发生动脉粥样硬化的血流动力学是否调节冠状动脉中 BMP 和 TNF(的表达)。目标#2：阐明易发生动脉粥样硬化的血流动力学、O2.-、H2O2 和/或 ONOO- 水平升高与内皮细胞和血管内促炎细胞因子表达之间的联系。平滑肌细胞。目标#3：确定易发生动脉粥样硬化的血流动力学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。目标#4：通过以下方式阐明其机制： BMP 引发内皮激活，促进冠状动脉中的单核细胞粘附。对这些参与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特定的治疗。预防 CAD 发展的干预措施。