Poly(ADP-ribose) polymerase inhibition combined with irradiation: a dual treatment concept to prevent neointimal hyperplasia after endarterectomy.
OBJECTIVE
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
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.
Beller
Carsten J
CJ
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. Carsten.Beller@urz.uni-heidelberg.de
Kosse
Jens
J
Radovits
Tamás
T
Gerö
Domokos
D
Krempien
Robert
R
Gross
Marie-Luise
ML
Berger
Irina
I
Hagl
Siegfried
S
Szabó
Csaba
C
Szabó
Gábor
G
D000818:Animals; D016894:Endarterectomy, Carotid / Q000009:adverse effects*; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007211:Indoles / Q000494:pharmacology; D008297:Male; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D011064:Poly Adenosine Diphosphate Ribose / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011829:Radiation Dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects
C491685:INO 1001; D007211:Indoles; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D030421:Peroxynitrous Acid; D011064:Poly Adenosine Diphosphate Ribose