Local lentiviral short hairpin RNA silencing of CCR2 inhibits vein graft thickening in hypercholesterolemic apolipoprotein E3-Leiden mice
| Autor: | Daniel Eefting, Theo J.C. Van Berkel, Ilze Bot, Margreet R. de Vries, Paul H.A. Quax, Abbey Schepers, Erik A.L. Biessen, J. Hajo van Bockel |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Male
Apolipoprotein E CCR2 Apolipoprotein B Receptors CCR2 Genetic enhancement Hypercholesterolemia Apolipoprotein E3 030204 cardiovascular system & hematology Gene delivery Veins Small hairpin RNA Mice 03 medical and health sciences 0302 clinical medicine Animals Medicine Chemokine CCL2 030304 developmental biology 0303 health sciences biology business.industry Lentivirus Graft Occlusion Vascular Cell migration Atherosclerosis 3. Good health Disease Models Animal Immunology cardiovascular system biology.protein Cancer research RNA Interference Surgery Cardiology and Cardiovascular Medicine Vein graft disease business |
| Zdroj: | Journal of Vascular Surgery. 50:152-160 |
| ISSN: | 0741-5214 |
| Popis: | ObjectiveInflammatory 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.MethodsA 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).ResultsVascular 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).ConclusionVascular 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.Clinical RelevanceVein graft disease is an important clinical issue that results from an inflammatory response. The monocyte chemoattractant protein (MCP)-1/CC-chemokine receptor (CCR)-2 pathway plays a key role in the initiation and development of vein graft disease. This study demonstrates that perivascular overexpression of short hairpin RNA, targeted against CCR2, inhibits vein graft thickening. These data show that organ-targeted gene therapy against CCR2 in the vessel wall could be a promising therapeutic tool to improve vein graft patency in bypassed patients. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|