Mb. Deyoung et al., Plasminogen activator inhibitor type I increases neointima formation in balloon-injured rat carotid arteries, CIRCULATION, 104(16), 2001, pp. 1972-1977
Citations number
30
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Background-Elevated plasma levels of plasminogen activator inhibitor type 1
(PAI-1) are associated with myocardial infarction, atherosclerosis, and re
stenosis. PAI-1 is increased in atherosclerotic arteries and failed vein gr
afts. No experimental data, however, support a causal relationship between
elevated PAI-1 expression and vascular lesions. Paradoxically, data generat
ed in PAI-1 knockout mice suggest that PAI-1 might decrease lesion formatio
n after arterial injury and that PAM 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 exp
ression would alter neointima formation. Compared with control-transduced a
rteries, neointima formation in PAI-1-transduced arteries was initially ret
arded. By 14 days, however, the intimas of PAI-1-transduced arteries were s
ignificantly larger than intimas of control-transduced arteries (1.6 +/-0.1
X 10(5) versus 1.2 +/-0.1 X 10(5) mum(2), n=18 to 19, P <0.03). PAI-1 expr
ession 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). PAM expression
also correlated with fibrin(ogen) accumulation (R=0.77, P <0.001), and fibr
in(ogen) accumulation correlated strongly with proliferation (R=0.86, P <0.
00001).
Conclusions-Increased expression of PAI-1 in the artery wall promotes neoin
tima growth after balloon injury. Therefore, despite encouraging data gener
ated in other animal models, PAI-1 is not a promising agent for gene therap
y to prevent restenosis. Moreover, our data associate elevated PAI-1 expres
sion 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.