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.

R01HL077256

2006-03-15

2011-02-28