Angiotensin converting enzyme inhibitor restrains inflammation-induced vascular injury in mice.
OBJECTIVE
Recent advances in molecular genetics made the mouse model important for studying the genetic basis of hypertension and vascular diseases such as the components of the renin-angiotensin system. This study was undertaken to investigate the role of angiotensin converting enzyme (ACE) in the mouse vascular injury model.


METHODS
Inflammation-induced vascular injury was created by placing a polyethylene cuff around the femoral artery of 12-14-week-old male FVB/N mice. Cuffed arteries were harvested and applied to reverse transcriptase-polymerase chain reaction analysis and immunohistochemistry for ACE. Subsequently, the effects of an ACE inhibitor, perindopril (3 mg/kg per day), on neointimal thickening were examined 2 weeks after cuff placement The influence of a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg per day) on the effects of perindopril was also examined.


RESULTS
ACE mRNA expression increased in a time-dependent manner up to 2 weeks after cuff placement. Immunoreactive ACE was localized in the endothelium in the intact artery, while positive staining was observed in the medial and neointimal layer as well as in the periadventitial region of the cuffed artery. The intimamedia area ratio was significantly decreased by perindopril treatment (vehicle, 0.75+/-0.10; perindopril, 0.32+/-0.04; P< 0.05). The effect of perindopril was abrogated by coadministration of L-NAME whereas L-NAME alone did not affect the intima-media ratio (L-NAME, 0.66+/-0.11; perindopril + L-NAME, 0.72+/-0.09).


CONCLUSIONS
This study provides evidence that ACE plays a role in cuff-induced neointimal thickening in mice. Nitric oxide may contribute, at least in part, to the inhibitory effects of perindopril.
Akishita
M
M
Cardiovascular Research, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Shirakami
G
G
Iwai
M
M
Wu
L
L
Aoki
M
M
Zhang
L
L
Toba
K
K
Horiuchi
M
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001808:Blood Vessels / Q000293:injuries*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005263:Femoral Artery / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D015870:Gene Expression; D007249:Inflammation / Q000150:complications / Q000517:prevention & control*; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000502:physiology; D020913:Perindopril / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D007703:Peptidyl-Dipeptidase A; D019331:NG-Nitroarginine Methyl Ester; D020913:Perindopril