doi: 10.1161/hc4101.097110
(Circulation. 2001;104:1972.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Plasminogen Activator Inhibitor Type 1 Increases Neointima Formation in Balloon-Injured Rat Carotid Arteries
From the Gladstone Institute of Cardiovascular Disease (M.B.D., C.T., D.A.D.), and Department of Medicine (D.A.D.), University of California, San Francisco, and the Department of Medicine (D.A.D.), University of Washington, Seattle.
Correspondence to Dr David A. Dichek, University of Washington, 1959 NE Pacific St, Box 357710, Seattle, WA 98195-7710. E-mail ddichek{at}u.washington.edu
Background— Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are associated with myocardial infarction, atherosclerosis, and restenosis. PAI-1 is increased in atherosclerotic arteries and failed vein grafts. No experimental data, however, support a causal relationship between elevated PAI-1 expression and vascular lesions. Paradoxically, data generated in PAI-1 knockout mice suggest that PAI-1 might decrease lesion formation after arterial injury and that PAI-1 gene transfer might prevent restenosis.
Methods and Results— Using the rat carotid balloon injury model and a PAI-1-expressing adenoviral vector, we tested whether elevated arterial PAI-1 expression would alter neointima formation. Compared with control-transduced arteries, neointima formation in PAI-1-transduced arteries was initially retarded. By 14 days, however, the intimas of PAI-1-transduced arteries were significantly larger than intimas of control-transduced arteries (1.6±0.1x105 versus 1.2±0.1x105 µm2, n=18 to 19, P<0.03). PAI-1 expression in individual arteries correlated with increased cell proliferation at 4 and 8 days after injury (R=0.6, P<0.02 and P<0.006). PAI-1 expression also correlated with fibrin(ogen) accumulation (R=0.77, P<0.001), and fibrin(ogen) accumulation correlated strongly with proliferation (R=0.86, P<0.00001).
Conclusions— Increased expression of PAI-1 in the artery wall promotes neointima growth after balloon injury. Therefore, despite encouraging data generated in other animal models, PAI-1 is not a promising agent for gene therapy to prevent restenosis. Moreover, our data associate elevated PAI-1 expression with fibrin(ogen) accumulation and increased cell proliferation. These data suggest a mechanism to explain the association between elevated PAI-1 expression and the progression of arterial disease.
Key Words: fibrinogen • gene therapy • restenosis • viruses • plasminogen activators
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