Inhibition of in-stent stenosis by oral administration of bindarit in porcine coronary arteries

A. Ialenti, G. Grassia, P. Gordon, M. Maddaluno, M. V. Di Lauro, A. H. Baker, A. Guglielmotti, A. Colombo, G. Biondi, S. Kennedy, Pasquale Maffia

Research output: Contribution to journalArticle

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Abstract

We have previously demonstrated that bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs), is effective in reducing neointimal formation in rodent models of vascular injury by reducing smooth muscle cell proliferation and migration and neointimal macrophage content, effects associated with the inhibition of MCP-1/CCL2 production. The aim of the current study was to evaluate the efficacy of bindarit on in-stent stenosis in the preclinical porcine coronary stent model.

One or 2 bare metal stents (Multi-Link Vision, 3.5 mm) were deployed (1: 1.2 oversize ratio) in the coronary arteries of 42 pigs (20 bindarit versus 22 controls). Bindarit (50 mg/kg per day) was administered orally from 2 days before stenting until the time of euthanasia at 7 and 28 days. Bindarit caused a significant reduction in neointimal area (39.4%, P < 0.001, n = 9 group), neointimal thickness (51%, P < 0.001), stenosis area (37%, P < 0.001), and inflammatory score (40%, P < 0.001) compared with control animals, whereas there was no significant difference in the injury score between the 2 groups. Moreover, treatment with bindarit significantly reduced the number of proliferating cells (by 45%, P < 0.05; n = 6 group) and monocyte/macrophage content (by 55%, P < 0.01; n = 5-6 group) in stented arteries at day 7 and 28, respectively. These effects were associated with a significant (P < 0.05) reduction of MCP-1 plasma levels at day 28. In vitro data showed that bindarit (10-300 mu mol/L) reduced tumor necrosis factor-alpha (50 ng/mL)-induced pig coronary artery smooth muscle cell proliferation and inhibited MCP-1 production.

Our results show the efficacy of bindarit in the prevention of porcine in-stent stenosis and support further investigation for clinical application of this compound. (Arterioscler Thromb Vasc Biol. 2011;31:2448-2454.)
LanguageEnglish
Pages2448-U230
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number11
DOIs
Publication statusPublished - Nov 2011

Fingerprint

Stents
Oral Administration
Coronary Vessels
Pathologic Constriction
Swine
Chemokine CCL2
Smooth Muscle Myocytes
Monocyte Chemoattractant Proteins
Macrophages
Cell Proliferation
Euthanasia
bindarit
Inhibition (Psychology)
Vascular System Injuries
Cell Movement
Monocytes
Rodentia
Arteries
Tumor Necrosis Factor-alpha
Cell Count

Keywords

  • animal-models
  • hyperplasia
  • restenosis
  • bindarit
  • neointima formation
  • pharmacology
  • monocyte chemoattractant protein-1
  • mcp-1 synthesis
  • protects mice
  • antiinflammatory agent bindarit
  • stent
  • local-delivery
  • chemotactic proteins

Cite this

Ialenti, A., Grassia, G., Gordon, P., Maddaluno, M., Di Lauro, M. V., Baker, A. H., ... Maffia, P. (2011). Inhibition of in-stent stenosis by oral administration of bindarit in porcine coronary arteries. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(11), 2448-U230. https://doi.org/10.1161/ATVBAHA.111.230078
Ialenti, A. ; Grassia, G. ; Gordon, P. ; Maddaluno, M. ; Di Lauro, M. V. ; Baker, A. H. ; Guglielmotti, A. ; Colombo, A. ; Biondi, G. ; Kennedy, S. ; Maffia, Pasquale. / Inhibition of in-stent stenosis by oral administration of bindarit in porcine coronary arteries. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 ; Vol. 31, No. 11. pp. 2448-U230.
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Ialenti, A, Grassia, G, Gordon, P, Maddaluno, M, Di Lauro, MV, Baker, AH, Guglielmotti, A, Colombo, A, Biondi, G, Kennedy, S & Maffia, P 2011, 'Inhibition of in-stent stenosis by oral administration of bindarit in porcine coronary arteries' Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 11, pp. 2448-U230. https://doi.org/10.1161/ATVBAHA.111.230078

Inhibition of in-stent stenosis by oral administration of bindarit in porcine coronary arteries. / Ialenti, A.; Grassia, G.; Gordon, P.; Maddaluno, M.; Di Lauro, M. V.; Baker, A. H.; Guglielmotti, A.; Colombo, A.; Biondi, G.; Kennedy, S.; Maffia, Pasquale.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 31, No. 11, 11.2011, p. 2448-U230.

Research output: Contribution to journalArticle

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T1 - Inhibition of in-stent stenosis by oral administration of bindarit in porcine coronary arteries

AU - Ialenti, A.

AU - Grassia, G.

AU - Gordon, P.

AU - Maddaluno, M.

AU - Di Lauro, M. V.

AU - Baker, A. H.

AU - Guglielmotti, A.

AU - Colombo, A.

AU - Biondi, G.

AU - Kennedy, S.

AU - Maffia, Pasquale

PY - 2011/11

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N2 - We have previously demonstrated that bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs), is effective in reducing neointimal formation in rodent models of vascular injury by reducing smooth muscle cell proliferation and migration and neointimal macrophage content, effects associated with the inhibition of MCP-1/CCL2 production. The aim of the current study was to evaluate the efficacy of bindarit on in-stent stenosis in the preclinical porcine coronary stent model. One or 2 bare metal stents (Multi-Link Vision, 3.5 mm) were deployed (1: 1.2 oversize ratio) in the coronary arteries of 42 pigs (20 bindarit versus 22 controls). Bindarit (50 mg/kg per day) was administered orally from 2 days before stenting until the time of euthanasia at 7 and 28 days. Bindarit caused a significant reduction in neointimal area (39.4%, P < 0.001, n = 9 group), neointimal thickness (51%, P < 0.001), stenosis area (37%, P < 0.001), and inflammatory score (40%, P < 0.001) compared with control animals, whereas there was no significant difference in the injury score between the 2 groups. Moreover, treatment with bindarit significantly reduced the number of proliferating cells (by 45%, P < 0.05; n = 6 group) and monocyte/macrophage content (by 55%, P < 0.01; n = 5-6 group) in stented arteries at day 7 and 28, respectively. These effects were associated with a significant (P < 0.05) reduction of MCP-1 plasma levels at day 28. In vitro data showed that bindarit (10-300 mu mol/L) reduced tumor necrosis factor-alpha (50 ng/mL)-induced pig coronary artery smooth muscle cell proliferation and inhibited MCP-1 production. Our results show the efficacy of bindarit in the prevention of porcine in-stent stenosis and support further investigation for clinical application of this compound. (Arterioscler Thromb Vasc Biol. 2011;31:2448-2454.)

AB - We have previously demonstrated that bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs), is effective in reducing neointimal formation in rodent models of vascular injury by reducing smooth muscle cell proliferation and migration and neointimal macrophage content, effects associated with the inhibition of MCP-1/CCL2 production. The aim of the current study was to evaluate the efficacy of bindarit on in-stent stenosis in the preclinical porcine coronary stent model. One or 2 bare metal stents (Multi-Link Vision, 3.5 mm) were deployed (1: 1.2 oversize ratio) in the coronary arteries of 42 pigs (20 bindarit versus 22 controls). Bindarit (50 mg/kg per day) was administered orally from 2 days before stenting until the time of euthanasia at 7 and 28 days. Bindarit caused a significant reduction in neointimal area (39.4%, P < 0.001, n = 9 group), neointimal thickness (51%, P < 0.001), stenosis area (37%, P < 0.001), and inflammatory score (40%, P < 0.001) compared with control animals, whereas there was no significant difference in the injury score between the 2 groups. Moreover, treatment with bindarit significantly reduced the number of proliferating cells (by 45%, P < 0.05; n = 6 group) and monocyte/macrophage content (by 55%, P < 0.01; n = 5-6 group) in stented arteries at day 7 and 28, respectively. These effects were associated with a significant (P < 0.05) reduction of MCP-1 plasma levels at day 28. In vitro data showed that bindarit (10-300 mu mol/L) reduced tumor necrosis factor-alpha (50 ng/mL)-induced pig coronary artery smooth muscle cell proliferation and inhibited MCP-1 production. Our results show the efficacy of bindarit in the prevention of porcine in-stent stenosis and support further investigation for clinical application of this compound. (Arterioscler Thromb Vasc Biol. 2011;31:2448-2454.)

KW - animal-models

KW - hyperplasia

KW - restenosis

KW - bindarit

KW - neointima formation

KW - pharmacology

KW - monocyte chemoattractant protein-1

KW - mcp-1 synthesis

KW - protects mice

KW - antiinflammatory agent bindarit

KW - stent

KW - local-delivery

KW - chemotactic proteins

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U2 - 10.1161/ATVBAHA.111.230078

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SP - 2448-U230

JO - Arteriosclerosis Thrombosis, and Vascular Biology

T2 - Arteriosclerosis Thrombosis, and Vascular Biology

JF - Arteriosclerosis Thrombosis, and Vascular Biology

SN - 1079-5642

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ER -