It is now well recognized that the clinical manifestations of coronary artery disease are due to a fundamental lapse in vascular homeostasis. This process begins with the rupture of an atherosclerotic plaque. Following this event, there is a cascade of events characterized by local platelet adhesion, platelet activation, thrombosis, and associated vasospasm. The precise molecular events that render an atherosclerotic plaque vulnerable to rupture are at present unknown. The purpose of this collaborative proposal is to help shed light on the molecular and physical mechanisms of plaque rupture. Convincing data demonstrate that plaque rupture is associated with vascular inflammation. Principal mediators of vascular inflammation are cell adhesion molecules and reactive oxygen species. Project 1 of this proposal will examine the relationship between cellular antioxidant status and the adhesiveness of inflammatory cells and platelets. This link between reactive oxygen species and the vulnerable plaque will be further extended to the process of thrombosis in Project 2 of this collaborative proposal. Because it is known that vulnerable plaques also possess specific physical characteristics, in Project 3 we will use an animal model of plaque rupture and atherosclerosis to correlate physical characteristics of vulnerable plaques, as defined by NMR spectroscopy and MRI, to their propensity for rupture. Finally, we will use the well characterized Framingham Heart Study population to examine the relationship between inflammatory markers of vascular disease and a well recognized surrogate marker of vascular disease, namely endothelial function. Using this multidisciplinary approach, we anticipate developing important new information to help shed light on the molecular mechanisms of plaque rupture, the associated physical characteristics of the vulnerable plaque, and the thrombotic and inflammatory responses to plaque rupture.
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