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; Szabó, Csaba; Szabó, Gábor

doi:10.1016/j.jvs.2005.11.021

Cited by 29 publications

(26 citation statements)

References 28 publications

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“…These results are not surprising, based on our previous data showing that PD128763 was unable to block SMC proliferation or migration in response to growth factor stimulation (Yau et al, 2003). In addition, these data suggest that ischemic injury is not a component of the vascular repair process, as has been previously suggested (Beller et al, 2006), although induction of hypoxia-inducible factor-1␣ after angioplasty has been observed (Karshovska et al, 2007). The slight inhibition in neointimal formation obtained with 3AB was concluded to represent inhibition of ART rather than PARP, as would be expected with the concentration that was used (Yau et al, 1998).…”

Section: Discussionsupporting

confidence: 81%

meta-Iodobenzylguanidine, an Inhibitor of Arginine-Dependent Mono(ADP-ribosyl)ation, Prevents Neointimal Hyperplasia

Yau

Molnar²,

Moon³

et al. 2008

J Pharmacol Exp Ther

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The association of ADP-ribosylation with cell proliferation and ischemia-reperfusion injury suggests that it may be a suitable target for therapeutic control of revascularization-induced injury. The purpose of this study was to investigate the inhibitory actions of ADP-ribosylation inhibitors on restenosis. In organ culture, the poly(ADP-ribose) polymerase (PARP) inhibitor 3,4-dihydro-5-methylisoquinolinone (PD128763) was unable to prevent neointimal hyperplasia, whereas the arginine-dependent mono(ADP-ribosyl)transferase (ART) inhibitor meta-iodobenzylguanidine (MIBG) was highly effective (EC 50 21 M). Treatment with 3-aminobenzamide (3AB), a less potent ART inhibitor, also produced a significant reduction in neointimal hyperplasia. Single doses (25 mM) of MIBG and 3AB were also applied within a fibrin coagulum directly to the adventitial surface of the porcine femoral artery after balloon catheter injury in vivo. MIBG reduced the neointimal index, measured 14 days after angioplasty, by 82%, whereas 3AB was ineffective. However, when extended to 45 days, the neointimal index was not significantly decreased by MIBG treatment relative to control. Assessment of MIBG release from the fibrin glue showed that the bulk of the compound was eluted within 3 days, suggesting that the vehicle was not suitable for long-term delivery. On the other hand, direct infusion of MIBG into vessels was able to reduce neointimal hyperplasia over 14 days in organ culture. These data support the conclusion that the cellular retention characteristics of MIBG contribute significantly to the efficacy of this compound. Based on these results, ART, but not PARP, may be a credible target for therapeutic treatment of restenosis.Revascularization procedures, such as balloon angioplasty, stenting, and bypass graft surgery, were developed for the treatment of coronary and peripheral arterial disease. These procedures effectively alleviate the symptoms that result from an arterial obstruction due to atherosclerosis (e.g., angina and claudication) and improve quality of life for these patients. Traditionally, the long-term efficacy of these procedures has been limited by restenosis, a reduction of the vascular lumen at the site of intervention. Restenosis rates of 20 to 50% were associated with balloon angioplasty and bare metal stents; however, the introduction of drug-eluting stents (DES) has reduced the incidence of restenosis to Ͻ10%

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Section: Discussionsupporting

confidence: 81%

meta-Iodobenzylguanidine, an Inhibitor of Arginine-Dependent Mono(ADP-ribosyl)ation, Prevents Neointimal Hyperplasia

Yau

Molnar²,

Moon³

et al. 2008

J Pharmacol Exp Ther

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“…19 Furthermore, PARP inhibition was shown to prevent neointimal hyperplasia after endarterectomy. 28 Therefore, it is conceivable that the effects of PARP inhibition on plaque number and size observed in the present study may be due in part to protective effects against endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 77%

“…19,28 Indeed, the early atherosclerotic functional alterations that develop in the endothelium of the ApoE Ϫ/Ϫ mice were shown to be dependent on the activation of PARP in endothelial cells. 19 Furthermore, PARP inhibition was shown to prevent neointimal hyperplasia after endarterectomy.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Inhibition Reduces Atherosclerotic Plaque Size and Promotes Factors of Plaque Stability in Apolipoprotein E–Deficient Mice

et al. 2007

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Background-Poly(ADP-ribose) polymerase (PARP) was suggested to play a role in endothelial dysfunction that is associated with a number of cardiovascular diseases. We hypothesized that PARP may play an important role in atherogenesis and that its inhibition may attenuate atherosclerotic plaque development in an experimental model of atherosclerosis. Methods and Results-Using a mouse (apolipoprotein E [ApoE]Ϫ/Ϫ ) model of high-fat diet-induced atherosclerosis, we demonstrate an association between cell death and oxidative stress-associated DNA damage and PARP activation within atherosclerotic plaques. PARP inhibition by thieno[2,3-c]isoquinolin-5-one reduced plaque number and size and altered structural composition of plaques in these animals without affecting sera lipid contents. These results were corroborated genetically with the use of ApoE Ϫ/Ϫ mice that are heterozygous for PARP-1. PARP inhibition promoted an increase in collagen content, potentially through an increase in tissue inhibitor of metalloproteinase-2, and transmigration of smooth muscle cells to intima of atherosclerotic plaques as well as a decrease in monocyte chemotactic protein-1 production, all of which are markers of plaque stability. In PARP-1 Ϫ/Ϫ macrophages, monocyte chemotactic protein-1 expression was severely inhibited because of a defective nuclear factor-B nuclear translocation in response to lipopolysaccharide. Furthermore, PARP-1 gene deletion not only conferred protection to foam cells against H 2 O 2 -induced death but also switched the mode of death from necrosis to apoptosis. Conclusions-Our results suggest that PARP inhibition interferes with plaque development and may promote plaque stability, possibly through a reduction in inflammatory factors and cellular changes related to plaque dynamics. PARP inhibition may prove beneficial for the treatment of atherosclerosis.

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“…7 In addition, evidence is growing that reduced nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling plays an important role in the pathogenesis of neointima formation, 8 which could be prevented by local delivery of NO 9 or by using a short-acting NO donor in the perivascular area of the injured rat carotid artery.…”

mentioning

confidence: 99%

“…6 Our previous studies showed that nitro-oxidative stress plays an important role in neointima formation after vascular injury, which could be effectively decreased by the inhibition of the peroxynitrite-poly (adenosine diphosphateribose) polymerase (PARP) pathway. 7 In addition, evidence is growing that reduced nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling plays an important role in the pathogenesis of neointima formation, 8 which could be prevented by local delivery of NO 9 or by using a short-acting NO donor in the perivascular area of the injured rat carotid artery. 10 Furthermore, neointimal proliferation could also be attenuated by endothelial NO synthase gene transfer in a rat model of balloon injury.…”

mentioning

confidence: 99%

Selective phosphodiesterase-5 inhibition reduces neointimal hyperplasia in rat carotid arteries after surgical endarterectomy

Hirschberg¹,

Radovits²,

Loganathan³

et al. 2009

Thorac cardiovasc Surg

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Objective: Long-term results of surgical vessel reconstruction are compromised by restenosis caused by neointimal hyperplasia. Recent studies suggest that reduced cyclic guanosine monophosphate signaling is associated with neointima formation. In a rat model of endarterectomy, we investigated the effect of pharmacologic inhibition of cyclic guanosine monophosphate degradation on neointima formation by using the selective phosphodiesterase-5 inhibitor vardenafil.Methods: Carotid endarterectomy was performed in male Sprague-Dawley rats by means of incision of the right common carotid artery with removal of intima. Four groups were studied: unoperated control rats (n ¼ 4), shamoperated rats (n ¼ 9), control rats with endarterectomy (n ¼ 9), or endarterectomized rats treated with vardenafil (10 mg/kg/day) postoperatively (n ¼ 9). After 3 weeks, vessel compartment areas were measured by means of conventional microscopy with hematoxylin and eosin staining. Immunohistochemical analysis was performed to confirm neointima formation and the local cyclic guanosine monophosphate content. Plasma levels of cyclic guanosine monophosphate were determined by means of enzyme immunoassay. Student's t test was used for statistical evaluation.Results: Immunohistochemical analysis demonstrated intensive staining for transforming growth factor b1 and a-smooth muscle actin in the control neointima. Vardenafil significantly reduced the stenosis grade (24.64% AE 7.46% vs 54.12% AE 10.30% in the control group, P<.05) and expression of transforming growth factor b1, as well as a-smooth muscle actin, in the neointima. The immunohistochemical score for cyclic guanosine monophosphate was higher in the treated neointima (4.80 AE 0.76 vs 2.84 AE 0.40 in the control group, P < .05), and increased plasma cyclic guanosine monophosphate levels were found by means of enzyme immunoassay as well (84.65 AE 12.77 pmol/mL vs 43.50 AE 3.30 pmol/mL in the control group, P < .05).Conclusions: Treatment with vardenafil can be considered a new possibility to prevent neointimal hyperplasia after endarterectomy.Carotid endarterectomy is the standard treatment of severe carotid stenosis.1 Operative repair is not without potential complications, one of which is postoperative restenosis. Despite technical problems, the main cause of early restenosis after surgical vessel reconstruction is neointimal hyperplasia. Risk factors for early restenosis include alterations in the complement system, 2 increased serum growth factor levels, 3 or changes in the hemostatic factors. Ischemia-reperfusion injury and endothelial damage promote neointima formation. In contrast with early restenosis, late restenosis is due to the progression of primary atherosclerosis. 5 Pathologically, the following processes contribute to early restenosis: the migration of smooth muscle cells (SMCs) from the medial to the intimal layer, the proliferation of SMCs, the deposition of extracellular matrix material, and alterations in apoptosis of neointimal cells. 6Our previous studies showed that nit...

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Activation of the peroxynitrite-poly(adenosine diphosphate-ribose) polymerase pathway during neointima proliferation: A new target to prevent restenosis after endarterectomy

Abstract: Pharmacologic inhibition of PARP with INO-1001 may be a new concept to prevent neointimal hyperplasia after endarterectomy.

Cited by 29 publications

References 28 publications

meta-Iodobenzylguanidine, an Inhibitor of Arginine-Dependent Mono(ADP-ribosyl)ation, Prevents Neointimal Hyperplasia

meta-Iodobenzylguanidine, an Inhibitor of Arginine-Dependent Mono(ADP-ribosyl)ation, Prevents Neointimal Hyperplasia

Poly(ADP-Ribose) Polymerase Inhibition Reduces Atherosclerotic Plaque Size and Promotes Factors of Plaque Stability in Apolipoprotein E–Deficient Mice

Selective phosphodiesterase-5 inhibition reduces neointimal hyperplasia in rat carotid arteries after surgical endarterectomy

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