ANGIOTENSIN-CONVERTING ENZYME-INHIBITION SUPPRESSES PLASMINOGEN-ACTIVATOR INHIBITOR-1 EXPRESSION IN THE NEOINTIMA OF BALLOON-INJURED RAT AORTA

Background Plasminogen activator inhibitor-1 (PAI-1), an important reg ulator of fibrinolysis and extracellular matrix turnover, has been imp licated in a number of vascular diseases. Studies demonstrating angiot ensin II (Ang II) to be a potent stimulator of PAI-1 expression in cul tured vascular cells suggests that the renin-angiotensin system may mo dulate vascular PAI-1 expression. Methods and Results We examined the effects of the ACE inhibitor captopril on PAI-1 expression in control and balloon-injured rat aorta. Northern blot analysis demonstrated tha t aortic PAI-1 mRNA expression was 7.6-fold elevated 3 hours (P<.05) a fter balloon injury, back to baseline at 2 days, increased again at 4 days, and by 7 days after balloon injury was 3.2-fold elevated (P<.05) when compared with control. In captopril-treated rats, the induction of PAI-1 expression by balloon injury was significantly suppressed by 44% (P<.05) in the 7-day group but was not altered in the 3-hour group . Captopril also reduced baseline aortic PAI-1 mRNA. In situ hybridiza tion and immunohistochemistry revealed dense PAI-1 staining of 7-day n eointima in untreated rats and a dramatic decrease in PAI-1 in neointi ma of captopril-treated rats. Conclusions This report demonstrates tha t balloon injury results in both a rapid ACE inhibitor-independent ind uction of aortic PAI-1 expression and a later increase in PAI-1 in the neointima that is significantly suppressed by captopril. This provide s the first evidence that the renin-angiotensin system regulates neoin timal PAI-1 expression and that ACE inhibitors can reduce PAI-1 in the vessel wall in vivo.