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 regulator of fibrinolysis and extracellular matrix turnover, has been implicated in a number of vascular diseases. Studies demonstrating angiotensin II (Ang II) to be a potent stimulator of PAI-1 expression in cultured vascular cells suggests that the renin-angiotensin system may modulate vascular PAI-1 expression.


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 that aortic PAI-1 mRNA expression was 7.6-fold elevated 3 hours (P<.05) after 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 hybridization and immunohistochemistry revealed dense PAI-1 staining of 7-day neointima in untreated rats and a dramatic decrease in PAI-1 in neointima of captopril-treated rats.


CONCLUSIONS
This report demonstrates that balloon injury results in both a rapid ACE inhibitor-independent induction of aortic PAI-1 expression and a later increase in PAI-1 in the neointima that is significantly suppressed by captopril. This provides the first evidence that the renin-angiotensin system regulates neointimal PAI-1 expression and that ACE inhibitors can reduce PAI-1 in the vessel wall in vivo.
Hamdan
A D
AD
Research Division of the Joslin Diabetes Center, Boston, MA 02215, USA.
Quist
W C
WC
Gagne
J B
JB
Feener
E P
EP
D000800:Angioplasty, Balloon; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism*; D002216:Captopril / Q000494:pharmacology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D000806:Angiotensin-Converting Enzyme Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D002216:Captopril