ACE-inhibition promotes apoptosis after balloon injury of rat carotid arteries.
OBJECTIVE
Angiotensin II stimulates vascular smooth muscle cell (VSMC) growth, and is considered to be an important mediator of intimal thickening after vascular injury. Recent evidence has indicated that VSMC apoptosis plays a major role in the response to balloon injury, and we therefore examined the effect of angiotensin converting enzyme (ACE)-inhibition on VSMC apoptosis and vascular lesion formation in the rat model of balloon injury.


METHODS
Male Sprague-Dawley rats were subjected to carotid artery balloon injury and randomised to a standard diet or a diet supplemented with 1 mg/ml captopril in the drinking water. Animals were sacrificed 2 and 14 days after injury for assessment of apoptosis and proliferation by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) and proliferating cell nuclear antigen (PCNA) immunohistochemistry, respectively. At 14 days post injury, vessel cross-sections were subjected to microscopic morphometry and total cell numbers were determined.


RESULTS
At 2 days after balloon injury, captopril-treated animals displayed a significant increase in the percentage of TUNEL-positive VSMCs in the medial area (12 +/- 4% vs. 1 +/- 1%; P < 0.05) as compared to controls. This increase in early apoptosis was associated with decreased intimal cellularity 14 days post injury (238 +/- 47 cells/cross-section vs. 449 +/- 75 cells/cross-section; P < 0.05), and a reduction of neointimal formation (0.13 +/- 0.02 mm2 vs. 0.23 +/- 0.04 mm2; P < 0.05). The fraction of PCNA-positive VSMCs per cross-section 2 or 14 days after injury was not significantly altered by captopril administration.


CONCLUSIONS
Captopril inhibits neointimal formation in the rat model of arterial injury by mechanisms involving induction of VSMC apoptosis.
Holm
A M
AM
Department of Medicine B2142, Rigshospital, Copenhagen, Denmark. amholm@hotmail.com
Andersen
C B
CB
Haunsø
S
S
Hansen
P R
PR
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002216:Captopril / Q000494:pharmacology*; D017536:Carotid Artery, Common / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D002455:Cell Division; D020287:In Situ Nick-End Labeling; D008297:Male; D008854:Microscopy, Electron; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000293:injuries* / Q000503:physiopathology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000473:pathology / Q000503:physiopathology
D000806:Angiotensin-Converting Enzyme Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D002216:Captopril