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Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 10, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp238
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

THE ANTI-INFLAMMATORY AGENT BINDARIT INHIBITS NEOINTIMA FORMATION IN BOTH RATS AND HYPERLIPIDEMIC MICE

Gianluca Grassia1, Marcella Maddaluno1, Angelo Guglielmotti2, Giorgina Mangano2, Giuseppe Biondi2, Pasquale Maffia1,3,4 and Armando Ialenti1,*

1 Department of Experimental Pharmacology, University of Naples Federico II, 80131 Naples, Italy
2 Angelini R&D, Angelini Research Center, 00040 S.Palomba-Pomezia, Rome, Italy
3 Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK
4 School of Biotechnological Sciences, University of Naples Federico II.

* Corresponding author: Prof. Armando Ialenti, Department of Experimental Pharmacology, University of Naples Federico II, Via Domenico , Montesano, 49, 80131 – Naples Italy, Tel. +39.081.678424; Fax +39.081.678403, e-mail: ialenti{at}unina.it

Aims: Bindarit is an original compound with peculiar anti-inflammatory activity due to a selective inhibition of a subfamily of inflammatory chemokines, including the monocyte chemotactic proteins MCP-1/CCL2, MCP-3/CCL7 and MCP-2/CCL8. In this study we investigated the effect of bindarit on neointima formation using two animal models of arterial injury: rat carotid artery balloon angioplasty and wire-induced carotid injury in apolipoprotein E-deficient (apoE–/-) mice.

Methods and Results: Treatment of rats with bindarit (200 mg/kg/day) significantly reduced balloon injury-induced neointima formation by 39% at day 14 without affecting re-endothelialization and reduced the number of medial and neointimal proliferating cells at day 7 by 54% and 30%, respectively. These effects were associated with a significant reduction of MCP-1 levels both in sera and in injured carotid arteries of rats treated with bindarit. In addition, in vitro data showed that bindarit (10-300 µM) reduced rat vascular smooth muscle cell (VSMC) proliferation, migration and invasion, processes contributing to the injury-induced neointima formation in vivo. Similar results were observed in hypercholesterolemic apoE–/- mice in which bindarit administration resulted in a 42% reduction of the number of proliferating cells at day 7 after carotid injury and in a 47% inhibition of neointima formation at day 28. Analysis of the cellular composition in neointimal lesions of apoE–/- mice treated with bindarit showed that the relative content of macrophages and the number of VSMCs were reduced by 66% and 30%, respectively, compared with the control group.

Conclusions: This study demonstrates that bindarit is effective in reducing neointima formation in both non-hyperlipidemic and hyperlipidemic animal models of vascular injury by a direct effect on VSMC proliferation and migration and by reducing neointimal macrophage content. All of these data were associated with the inhibition of MCP-1 production.

Time for primary review: 26 Days


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