The anti-inflammatory agent bindarit inhibits neointima formation in both rats and hyperlipidaemic mice.
OBJECTIVE
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.


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 microM) 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 hypercholesterolaemic 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-hyperlipidaemic and hyperlipidaemic 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.
Grassia
Gianluca
G
Department of Experimental Pharmacology, University of Naples Federico II, Via Domenico Montesano, 49, 80131 Naples, Italy.
Maddaluno
Marcella
M
Guglielmotti
Angelo
A
Mangano
Giorgina
G
Biondi
Giuseppe
G
Maffia
Pasquale
P
Ialenti
Armando
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006949:Hyperlipidemias / Q000378:metabolism / Q000473:pathology*; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D007191:Indazoles; D011422:Propionates; C079489:bindarit