FUNCTION OF MATRIX METALLOPROTEINASES AND HEPARIN

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Controlled remodeling is an essential feature of blood vessel growth and development as well as the pathological response to disease. Although much of the focus of vascular biological research has been on factors that increase wall mass by stimulating the accumulation of smooth muscle cells and matrix, we propose that factors controlling atrophy and degradation of matrix are of equal importance. Such factors might be critical determinants of atherosclerotic plaque rupture and excessive intimal thickening after vascular reconstruction. The primary objective of this research program will be to test two hypotheses: 1. matrix metalloproteinases (MMPs) are required for arterial smooth muscle cell migration and proliferation as well as matrix turnover in injured and atherosclerotic arteries; 2. heparin inhibits SMC function by interfering with the transcription of interstitial collagenase as well as several other matrix-degrading proteases. The experiments will define the role of MMPs in rat SMC function in vitro and in injured carotid artery using a novel pharmacological approach with cells transduced with replication- defective retroviral vectors overexpressing the major inhibitor of MMPs, tissue inhibitor of metalloproteinase-1. We will attempt to define a role for interstitial collagenase in atherosclerosis by studying the expression of this protease in a monkey model of atherogenesis and in advanced human carotid artery plaques that exhibit fibrous cap disruption and hemorrhage. Parallel experiments will attempt to define where heparin acts to control collagenase transcription (protein kinase C/AP-1 pathway) in baboon and rat SMCs in vitro and in vivo; the focus will initially be on regulation of MAP kinase and Jun B expression.