Activation of the peroxynitrite-poly(adenosine diphosphate-ribose) polymerase pathway during neointima proliferation: a new target to prevent restenosis after endarterectomy.
OBJECTIVE
In a rat model of endarterectomy, we investigated the potential role of the peroxynitrite-poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) pathway in neointima formation and the effect of pharmacologic inhibition of PARP on vascular remodeling.


METHODS
Carotid endarterectomy was performed in male Sprague-Dawley rats by incision of the left carotid artery with removal of intima. Three groups were studied: sham-operated rats (n = 10), control rats with endarterectomy (n = 10) or rats with endarterectomy treated with the PARP inhibitor, INO-1001 (5 mg/kg daily) postoperatively (n =10). After 21 days, neointima formation and vascular remodeling were assessed.


RESULTS
Immunohistochemistry analysis demonstrated activation of the peroxynitrite-PARP pathway with significant staining for nitrotyrosine, poly(ADP-ribose), and nuclear translocation of apoptosis-inducing factor (AIF) in the neointima of the control group. Treatment with INO-1001 significantly reduced the neointima area (0.024 mm2 +/- 0.019 mm2 vs 0.089 mm2 +/- 0.033 mm2 in the control group), the neointima/media thickness ratio (0.81 +/- 0.05 vs 2.76 +/- 1.57 in the control group), and the inflammation score (0.1 +/- 0.07 vs 0.3 +/- 0.12 in the control group) after endarterectomy.


CONCLUSIONS
Pharmacologic inhibition of PARP with INO-1001 may be a new concept to prevent neointimal hyperplasia after endarterectomy.
Beller
Carsten J
CJ
Department of Cardiac Surgery, University of Heidelberg, Germany. Carsten.Beller@urz.uni-heidelberg.de
Radovits
Tamás
T
Kosse
Jens
J
Gerö
Domokos
D
Szabó
Csaba
C
Szabó
Gábor
G
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000818:Animals; D001707:Biopsy, Needle; D016893:Carotid Stenosis / Q000473:pathology / Q000601:surgery; D003251:Constriction, Pathologic / Q000517:prevention & control; D004195:Disease Models, Animal; D004691:Endarterectomy / Q000009:adverse effects / Q000379:methods*; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D012016:Reference Values; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*
C491685:INO 1001; D007211:Indoles; D030421:Peroxynitrous Acid; D000246:Adenosine Diphosphate Ribose