Poly(ADP-ribose) polymerase inhibition combined with irradiation: A dual treatment concept to prevent neointimal hyperplasia after endarterectomy

Carsten J. Beller, Jens Kosse, T. Radovits, Domokos Gerö, Robert Krempien, Marie Luise Gross, Irina Berger, Siegfried Hagl, Csaba Szabó, G. Szabó

Research output: Contribution to journalArticle

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Abstract

Purpose: In a rat model of endarterectomy we investigated the potential role of the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway in neointima formation and the effects of irradiation, pharmacologic inhibition of PARP, or combined pharmacologic inhibition of PARP and irradiation on vascular remodeling. Methods and Materials: Carotid endarterectomy was performed by incision of the left carotid artery with removal of intima in Sprague-Dawley rats. Six groups were studied: sham-operated rats (n = 10), control endarterectomized rats (n = 10), or endarterectomized rats irradiated with 15 Gy (n = 10), or treated with PARP inhibitor, INO-1001 (5 mg/kg/day) (n = 10), or with combined treatment with INO-1001 and irradiation with 5 Gy (n = 10) or with 15 Gy (n = 10). After 21 days, neointima formation and vascular remodeling were assessed. Results: Neointima formation after endarterectomy was inhibited by postoperative irradiation with 15 Gy and was attenuated by PARP inhibition. However, in parallel to inhibition of neointimal hyperplasia, activation of the peroxynitrite-PARP pathway in the outer vessel wall layers was triggered by postoperative irradiation. Combined pharmacologic PARP inhibition and irradiation with 15 Gy significantly reduced both neointimal hyperplasia and activation of the peroxynitrite-PARP pathway in the outer vessel wall layers. Combination of PARP inhibition and irradiation with 5 Gy was less effective than both PARP inhibition or irradiation with 15 Gy alone. Conclusions: We conclude, that combined PARP inhibition and irradiation with 15 Gy may be a new dual strategy for prevention of restenosis after surgical vessel reconstruction: combining the strong antiproliferative effect of irradiation and ameliorating irradiation-induced side effects caused by excessive PARP activation.

Original languageEnglish
Pages (from-to)867-875
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume66
Issue number3
DOIs
Publication statusPublished - Nov 1 2006

Fingerprint

ribose
adenosine diphosphate
Endarterectomy
Poly(ADP-ribose) Polymerases
Hyperplasia
irradiation
rats
Neointima
Peroxynitrous Acid
vessels
activation
Carotid Endarterectomy
Carotid Arteries
arteries
Sprague Dawley Rats
inhibitors

Keywords

  • Endarterectomy
  • Irradiation
  • Neointima
  • Nitrosative stress
  • PARP inhibition

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

Cite this

Poly(ADP-ribose) polymerase inhibition combined with irradiation : A dual treatment concept to prevent neointimal hyperplasia after endarterectomy. / Beller, Carsten J.; Kosse, Jens; Radovits, T.; Gerö, Domokos; Krempien, Robert; Gross, Marie Luise; Berger, Irina; Hagl, Siegfried; Szabó, Csaba; Szabó, G.

In: International Journal of Radiation Oncology Biology Physics, Vol. 66, No. 3, 01.11.2006, p. 867-875.

Research output: Contribution to journalArticle

Beller, Carsten J. ; Kosse, Jens ; Radovits, T. ; Gerö, Domokos ; Krempien, Robert ; Gross, Marie Luise ; Berger, Irina ; Hagl, Siegfried ; Szabó, Csaba ; Szabó, G. / Poly(ADP-ribose) polymerase inhibition combined with irradiation : A dual treatment concept to prevent neointimal hyperplasia after endarterectomy. In: International Journal of Radiation Oncology Biology Physics. 2006 ; Vol. 66, No. 3. pp. 867-875.
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T2 - A dual treatment concept to prevent neointimal hyperplasia after endarterectomy

AU - Beller, Carsten J.

AU - Kosse, Jens

AU - Radovits, T.

AU - Gerö, Domokos

AU - Krempien, Robert

AU - Gross, Marie Luise

AU - Berger, Irina

AU - Hagl, Siegfried

AU - Szabó, Csaba

AU - Szabó, G.

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N2 - Purpose: In a rat model of endarterectomy we investigated the potential role of the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway in neointima formation and the effects of irradiation, pharmacologic inhibition of PARP, or combined pharmacologic inhibition of PARP and irradiation on vascular remodeling. Methods and Materials: Carotid endarterectomy was performed by incision of the left carotid artery with removal of intima in Sprague-Dawley rats. Six groups were studied: sham-operated rats (n = 10), control endarterectomized rats (n = 10), or endarterectomized rats irradiated with 15 Gy (n = 10), or treated with PARP inhibitor, INO-1001 (5 mg/kg/day) (n = 10), or with combined treatment with INO-1001 and irradiation with 5 Gy (n = 10) or with 15 Gy (n = 10). After 21 days, neointima formation and vascular remodeling were assessed. Results: Neointima formation after endarterectomy was inhibited by postoperative irradiation with 15 Gy and was attenuated by PARP inhibition. However, in parallel to inhibition of neointimal hyperplasia, activation of the peroxynitrite-PARP pathway in the outer vessel wall layers was triggered by postoperative irradiation. Combined pharmacologic PARP inhibition and irradiation with 15 Gy significantly reduced both neointimal hyperplasia and activation of the peroxynitrite-PARP pathway in the outer vessel wall layers. Combination of PARP inhibition and irradiation with 5 Gy was less effective than both PARP inhibition or irradiation with 15 Gy alone. Conclusions: We conclude, that combined PARP inhibition and irradiation with 15 Gy may be a new dual strategy for prevention of restenosis after surgical vessel reconstruction: combining the strong antiproliferative effect of irradiation and ameliorating irradiation-induced side effects caused by excessive PARP activation.

AB - Purpose: In a rat model of endarterectomy we investigated the potential role of the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway in neointima formation and the effects of irradiation, pharmacologic inhibition of PARP, or combined pharmacologic inhibition of PARP and irradiation on vascular remodeling. Methods and Materials: Carotid endarterectomy was performed by incision of the left carotid artery with removal of intima in Sprague-Dawley rats. Six groups were studied: sham-operated rats (n = 10), control endarterectomized rats (n = 10), or endarterectomized rats irradiated with 15 Gy (n = 10), or treated with PARP inhibitor, INO-1001 (5 mg/kg/day) (n = 10), or with combined treatment with INO-1001 and irradiation with 5 Gy (n = 10) or with 15 Gy (n = 10). After 21 days, neointima formation and vascular remodeling were assessed. Results: Neointima formation after endarterectomy was inhibited by postoperative irradiation with 15 Gy and was attenuated by PARP inhibition. However, in parallel to inhibition of neointimal hyperplasia, activation of the peroxynitrite-PARP pathway in the outer vessel wall layers was triggered by postoperative irradiation. Combined pharmacologic PARP inhibition and irradiation with 15 Gy significantly reduced both neointimal hyperplasia and activation of the peroxynitrite-PARP pathway in the outer vessel wall layers. Combination of PARP inhibition and irradiation with 5 Gy was less effective than both PARP inhibition or irradiation with 15 Gy alone. Conclusions: We conclude, that combined PARP inhibition and irradiation with 15 Gy may be a new dual strategy for prevention of restenosis after surgical vessel reconstruction: combining the strong antiproliferative effect of irradiation and ameliorating irradiation-induced side effects caused by excessive PARP activation.

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KW - Irradiation

KW - Neointima

KW - Nitrosative stress

KW - PARP inhibition

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