Plasminogen activator inhibitor type 1 increases neointima formation in balloon-injured rat carotid arteries.
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.


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+/-0.1x10(5) versus 1.2+/-0.1x10(5) micrometer(2), 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.
DeYoung
M B
MB
Gladstone Institute of Cardiovascular Disease, Department of Medicine, University of California, San Francisco, USA.
Tom
C
C
Dichek
D A
DA
D000256:Adenoviridae / Q000235:genetics; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D002340:Carotid Artery Diseases / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005337:Fibrin / Q000378:metabolism; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007150:Immunohistochemistry; D017395:Plasminogen Activator Inhibitor 1 / Q000008:administration & dosage* / Q000235:genetics; D051381:Rats; D014161:Transduction, Genetic; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology
D017395:Plasminogen Activator Inhibitor 1; D005337:Fibrin