Activation of the peroxynitrite-poly(adenosine diphosphate-ribose) polymerase pathway during neointima proliferation

A new target to prevent restenosis after endarterectomy

Carsten J. Beller, Tamás Radovits, Jens Kosse, Domokos Gerö, Csaba Szabo, Gábor Szabó

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)824-830
Number of pages7
JournalJournal of Vascular Surgery
Volume43
Issue number4
DOIs
StatePublished - Apr 2006
Externally publishedYes

Fingerprint

Poly Adenosine Diphosphate Ribose
Neointima
Endarterectomy
Peroxynitrous Acid
Control Groups
Apoptosis Inducing Factor
Activation Analysis
Poly(ADP-ribose) Polymerases
Carotid Endarterectomy
Carotid Arteries
Hyperplasia
Sprague Dawley Rats
Immunohistochemistry
Staining and Labeling
Inflammation
INO 1001

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Activation of the peroxynitrite-poly(adenosine diphosphate-ribose) polymerase pathway during neointima proliferation : A new target to prevent restenosis after endarterectomy. / Beller, Carsten J.; Radovits, Tamás; Kosse, Jens; Gerö, Domokos; Szabo, Csaba; Szabó, Gábor.

In: Journal of Vascular Surgery, Vol. 43, No. 4, 04.2006, p. 824-830.

Research output: Contribution to journalArticle

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abstract = "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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