TY - JOUR
T1 - Activation of the peroxynitrite-poly(adenosine diphosphate-ribose) polymerase pathway during neointima proliferation
T2 - A new target to prevent restenosis after endarterectomy
AU - Beller, Carsten J.
AU - Radovits, Tamás
AU - Kosse, Jens
AU - Gerö, Domokos
AU - Szabó, Csaba
AU - Szabó, Gábor
N1 - Funding Information:
This work was supported by a grant from the German Research Foundation (SFB 414) to C. J. B. and G. S., and a grant from the Hungarian Research Fund (OTKA M041541) to C. S.
PY - 2006/4
Y1 - 2006/4
N2 - 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 mm 2 ± 0.019 mm 2 vs 0.089 mm 2 ± 0.033 mm 2 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.
AB - 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 mm 2 ± 0.019 mm 2 vs 0.089 mm 2 ± 0.033 mm 2 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.
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U2 - 10.1016/j.jvs.2005.11.021
DO - 10.1016/j.jvs.2005.11.021
M3 - Article
C2 - 16616243
AN - SCOPUS:33645730486
SN - 0741-5214
VL - 43
SP - 824
EP - 830
JO - Journal of vascular surgery
JF - Journal of vascular surgery
IS - 4
ER -