Print Email Facebook Twitter Local lentiviral short hairpin RNA silencing of CCR2 inhibits vein graft thickening in hypercholesterolemic apolipoprotein E3-Leiden mice Title Local lentiviral short hairpin RNA silencing of CCR2 inhibits vein graft thickening in hypercholesterolemic apolipoprotein E3-Leiden mice Author Eefting, D. Bot, I. de Vries, M.R. Schepers, A. van Bockel, J.H. van Berkel, T.J.C. Biessen, E.A.L. Quax, P.H.A. TNO Kwaliteit van Leven Publication year 2009 Abstract Objective: Inflammatory responses to vascular injury are key events in vein graft disease and accelerated atherosclerosis, which may result in bypass failure. The monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine receptor (CCR)-2 pathway is hypothesized to play a central role. A murine model for vein graft disease was used to study the effect of local application of lentiviral short hairpin RNA (shRNA) targeted against CCR2. Methods: A venous interposition was placed into the carotid artery of hypercholesterolemic apolipoprotein E3-Leiden (APOE*3-Leiden) mice to induce vein graft thickening with features of accelerated atherosclerosis. To demonstrate the efficacy of the lentiviral shRNA targeting murine CCR2 (shCCR2) in blocking vein graft disease in vivo, lentiviral shCCR2 or a control lentivirus was used to infect the vein graft locally (n = 8). Results: Vascular CCR2 and MCP-1 messenger RNA expression levels were significantly upregulated during lesion progression in the vein graft. Infection of smooth muscle cells (SMCs) with a lentiviral shRNA targeting shCCR2 completely abolished MCP-1-induced SMC migration and inhibited SMC proliferation in vitro (n = 3 per group). Morphometric analysis of sections of grafts showed a significant 38% reduction in vein graft thickening in the shCCR2-treated mice 4 weeks after surgery (control, 0.42 ± 0.05 mm2; shCCR2, 0.26 ± 0.03 mm2; P = .007). Conclusion: Vascular CCR2 contributes to vein graft disease, and local application of shRNA against CCR2 to the vessel wall prevents vein graft thickening in hypercholesterolemic mice, suggesting that local overexpressing of shRNA using organ-targeted lentiviral gene delivery may be a promising therapeutic tool to improve vein graft disease in bypassed patients. © 2009 Society for Vascular Surgery. Subject BiologyBiomedical Researchapolipoprotein E3chemokine receptor CCR2lentiviral short hairpin RNAlentivirus vectormessenger RNAmonocyte chemotactic protein 1unclassified druganimal cellanimal modelarticleatherosclerosiscarotid arterycell migrationcell proliferationclinical featurecontrolled studydisease coursedrug delivery systemdrug efficacydrug targetinggene silencinggene therapyhypercholesterolemiain vitro studyin vivo studyinfectionLentivirinaemalemorphometricsmousenonhumanpriority journalprotein expressionreceptor upregulationsmooth muscle fibertreatment outcomevein graftvein graft diseasevein surgeryviral gene delivery systemAnimalsApolipoprotein E3AtherosclerosisChemokine CCL2Disease Models, AnimalGraft Occlusion, VascularHypercholesterolemiaLentivirusMaleMiceReceptors, CCR2RNA InterferenceVeins To reference this document use: http://resolver.tudelft.nl/uuid:f8bfa166-7aa9-420e-bdc5-66cb2d1d4c0b DOI https://doi.org/10.1016/j.jvs.2009.03.027 TNO identifier 241609 ISSN 0741-5214 Source Journal of Vascular Surgery, 50 (1), 152-160 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.