Angiotensin converting enzyme inhibition prevents proto-oncogene expression in the vascular wall after injury.
OBJECTIVE
Angiotensin converting enzyme (ACE) inhibitors reduce neointimal hyperplasia after balloon denudation, but the mechanisms are not completely understood. It has been demonstrated that nuclear oncogenes are induced in the vascular wall in the hours immediately after injury, and that the same genes are induced by angiotensin II in vascular smooth muscle cells. It has therefore been suggested that the effects of ACE inhibitors on the response of the vessel wall could be mediated by an inhibition of proto-oncogene expression.


RESULTS
Sixteen New Zealand White rabbits were randomly assigned for histologic analysis to receive placebo (n = 9) or 1 mg/kg per day perindopril (n = 7). After treatment for 7 days balloon aortic injury was performed. The treatment was continued and the rabbits were killed 28 days after injury. In the perindopril group the neointimal cross-sectional area was significantly smaller than in the control group. Six untreated rabbits were used to assess the time course of proto-oncogene expression in the aortic wall after injury in the present model. After extraction, total aortic RNA was hybridized with myc, fos and jun probes. Based on the results, the effects of ACE inhibition on proto-oncogene expression were tested 1 h after balloon denudation. Accordingly, 24 rabbits were randomly assigned to pretreatment for 7 days with placebo or with 1 or 10 mg/kg per day perindopril (n = 8, for each group) and were killed 1 h after injury. Expression of c-myc was not altered by pretreatment. However, 1 mg/kg per day perindopril induced significant reductions of 50% in c-jun and 45% in c-fos expression compared with control. No additional effect was obtained with the higher dose.


CONCLUSIONS
The effect of ACE inhibition on intimal hyperplasia is associated with a reduction in early cellular events such as c-fos and c-jun expression. These results suggest that potent ACE inhibition at the time of vascular injury may be required to limit the hyperplastic response of the vessel wall.
Van Belle
E
E
Department of Cardiology, University of Lille, France.
Bauters
C
C
Wernert
N
N
Delcayre
C
C
McFadden
E P
EP
Dupuis
B
B
Lablanche
J M
JM
Bertrand
M E
ME
Swynghedauw
B
B
D000818:Animals; D001011:Aorta; D015152:Blotting, Northern; D002404:Catheterization / Q000009:adverse effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000201:enzymology / Q000293:injuries* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006965:Hyperplasia / Q000235:genetics; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects*; D020913:Perindopril; D011519:Proto-Oncogenes / Q000187:drug effects* / Q000235:genetics; D011817:Rabbits; D011897:Random Allocation
D007211:Indoles; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril