The effects of PPARγ agonist rosiglitazone on neointimal hyperplasia in rabbit carotid anastomosis model

Mehmet Guzeloglu,Alper Bagrıyanık,Soner Atmaca,Buket Reel,Eyup Hazan

doi:10.1186/1749-8090-7-57

Abstract

BackgroundNeointimal hyperplasia involving smooth muscle cell (SMC) proliferation, migration and extracellular matrix (ECM) degradation is an important component of atherosclerosis. It develops as a response to vascular injury after balloon angioplasty and vascular graft placement. Matrix metalloproteinases (MMPs) induce SMC proliferation, migration and contribute to intimal hyperplasia by degrading ECM. PPARγ agonists inhibit SMC proliferation, migration and lesion formation. In this study, we aimed to investigate the effects of PPARγ agonist rosiglitazone on neointimal hyperplasia and gelatinase (MMP-2 and MMP-9) expressions in rabbit carotid anastomosis model.MethodsNew Zealand white rabbits (n = 13, 2.7–3.2 kg) were divided into placebo and treatment groups. Right carotid artery (CA) was transected and both ends were anastomosed. Treatment group (n = 6) received rosiglitazone (3 mg/kg/day/p.o.) and placebo group (n = 7) received PBS (phosphate buffered saline, 2.5 ml/kg/day/p.o.) for 4 weeks postoperatively. After the sacrification, right and left CAs were isolated. Morphometric analyses and immunohistochemical examinations for gelatinases were performed.ResultsIntimal area (0.055 ± 0.005 control vs 0.291 ± 0.020 μm2 anastomosed, p < 0,05) and index (0.117 ± 0.002 control vs 0.574 ± 0.013 anastomosed, p < 0,01) significantly increased in anastomosed arteries compared to control arteries from placebo group. However, in rosiglitazone-treated group, intimal area (0.291 ± 0.020 PBS vs 0.143 ± 0.027 rosiglitazone, p < 0,05) and index (0.574 ± 0.013 PBS vs 0.263 ± 0.0078 rosiglitazone, p < 0,01) significantly decreased. Furthermore, gelatinase immunopositivity was found to have significantly increased in anastomosed arteries from placebo group and decreased with rosiglitazone treatment.ConclusionsThese results suggest that rosiglitazone may prevent neointimal hyperplasia, which is the most important factor involved in late graft failure, by inhibiting gelatinase enzyme expression.

Highlights

Neointimal hyperplasia involving smooth muscle cell (SMC) proliferation, migration and extracellular matrix (ECM) degradation is an important component of atherosclerosis
Immunoscoring for Matrix metalloproteinases (MMPs)-2 and MMP-9 showed that rosiglitazone treatment significantly decreased immunopositivity for these two proteins in anastomosed right carotid arteries compared to placebo group (Figure 6, Table 1)
In the present study we showed that carotid artery anastomosis model leads to intensive neointimal hyperplasia and increased intima/media index in rabbits from placebo group consistent with our previous findings [20]

Summary

Introduction

Neointimal hyperplasia involving smooth muscle cell (SMC) proliferation, migration and extracellular matrix (ECM) degradation is an important component of atherosclerosis. Neointimal hyperplasia has a major role in early restenosis after surgical interventions such as surgical revascularisation, percutan transluminal angioplasty (PTA) and stenting [1,2] It is an early and essential step in the pathogenesis of atherosclerosis and restenosisis. This step is characterised by extracellular matrix (ECM) degradation, and medial vascular smooth muscle cell migration to intima and their proliferation. Matrix metalloproteases (MMPs) are a family of zincdependent enzymes which induce smooth muscle proliferation and migration by degrading ECM and contribute to intimal hyperplasia, inflamation and plaque rupture [3]. The three PPAR isotypes, PPAR-α, PPAR-δ and PPAR-γ modulate the function of many target genes and participate in the regulation of vital processes such as inflammation, cell growth, proliferation, migration and differentiation [4,5,6]

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