Local lentiviral short hairpin RNA silencing of CCR2 inhibits vein graft thickening in hypercholesterolemic apolipoprotein E3-Leiden mice

Autor: Eefting, D., Bot, I., Vries, M.R. de, Schepers, A., Bockel, J.H. van, Berkel, T.J.C. van, Biessen, E.A.L., Quax, P.H.A.
Přispěvatelé: TNO Kwaliteit van Leven
Jazyk: angličtina
Rok vydání: 2009
Předmět:
Male
Biomedical Research
cell migration
chemokine receptor CCR2
Apolipoprotein E3
animal cell
gene silencing
Mice
vein surgery
drug delivery system
receptor upregulation
Chemokine CCL2
hypercholesterolemia
morphometrics
messenger RNA
disease course
article
Graft Occlusion
Vascular
gene therapy
unclassified drug
priority journal
cardiovascular system
RNA Interference
lentivirus vector
monocyte chemotactic protein 1
Lentivirinae
in vitro study
Receptors
CCR2
Veins
in vivo study
Animals
controlled study
Biology
protein expression
mouse
nonhuman
carotid artery
animal model
vein graft disease
Lentivirus
drug targeting
Atherosclerosis
infection
clinical feature
drug efficacy
Disease Models
Animal
cell proliferation
lentiviral short hairpin RNA
smooth muscle fiber
treatment outcome
vein graft
viral gene delivery system
Zdroj: Journal of Vascular Surgery, 1, 50, 152-160
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: