Plasminogen activator inhibitor - 1 (PAI-1) is the major physiologic inhibitor of tissue and urokinase-type plasminogen activators, which regulate plasmin-mediated proteolysis. PAI-1 accumulation is observed in human atherosclerotic lesions and increased plasma levels of PAI-1 correlate with an increased incidence of myocardial infarction and restenosis. Despite these compelling observations, evidence of a casual role for PAI-1 in cardiovascular disease is circumstantial. In this study, we will test the hypothesis that increased PAI-1 expression directly modifies vascular remodeling after injury. To do this, PAI-1 expression will be specifically increased by transducing balloon-injured rat carotid arteries with an adenovirus expressing rat PAI-1. Preliminary studies have shown that arterial gene transfer of PAI-1 increases neointimal formation.
Specific Aim 1 : To determine the mechanism by which PAI-1 overexpression increases neointimal formation. The arteries will be assayed for increased fibrin deposition, extracellular matrix synthesis, smooth muscle cell (SMC) proliferation, SMC migration, and/or reduced SMC apoptosis.
Specific Aim 2 : To determine whether serpin activity, vitronectin binding or both are required for PAI-1 to increase neointimal formation. Mutant PAI-1 molecules that lack serpin or vitronectin binding activity will be expressed in the artery wall and the resultant phenotypes characterized. These studies will define the role of PAI-1 in vascular remodeling. The results may have implications for understanding the pathogenesis of restenosis and atheroma formation.
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| DeYoung, M B; Tom, C; Dichek, D A (2001) Plasminogen activator inhibitor type 1 increases neointima formation in balloon-injured rat carotid arteries. Circulation 104:1972-1 |
| DeYoung, M B; Zamarron, C; Lin, A P et al. (1999) Optimizing vascular gene transfer of plasminogen activator inhibitor 1. Hum Gene Ther 10:1469-78 |
