Cardiovascular diseases have atherosclerosis as their primary underlying cause and obesity as a major risk factor. One of the influential variables implicated in both human and mouse models of atherosclerosis and of obesity is the plasminogen system. Components of the plasminogen system are found within atherosclerosis lesions, and it has long been appreciated that the hyprofibrinolysis found in obesity is associated with cardiovascular disease. although these observations clearly link the plasminogen system to atherosclerosis and obesity, facile and systemic approaches to evaluate the function and variability of this system are unavailable. The objective of this proposal to establish a protocol for the efficient and rapid screening of the plasminogen system and its function in transgenic, gene-targeted, and inbred mice which are currently being used as models of atherosclerosis and obesity. The following specific aims are proposed: (1) establish and test a protocol to systematically evaluate the function of the plasminogen system in mice. This protocol will include assessment of the plasminogen system response of in vivo challenges and quantitation of antigens and activities for specific components of the plasminogen system; (2) using this protocol, evaluate the function of the plasminogen system in inbred mouse strains with differential susceptibility to development of atherosclerotic lesions and differential susceptibility to diet-induced obesity; and (3) using the developed protocol, evaluate the function of the plasminogen system in representative transgenic, gene-targeted, and single-gene mutation mouse models which develop atherosclerosis or obesity. The evaluation of variation in the plasminogen system in mice has not been undertaken in a systematic fashion. The development and testing of a protocol for critical assessment of plasminogen function would provide a useful tool for analyzing its role in other mouse models of disease. The proposed studies have the potential to lead to novel insights into the development of atherosclerosis and the role of obesity in the development of cardiovascular diseases and may lead to new targets for prevention and therapy. (End of Abstract.)
