Anti-MCP-1 gene therapy inhibits vascular smooth muscle cells proliferation and attenuates vein graft thickening both in vitro and in vivo
article
OBJECTIVE - Because late vein graft failure is caused by intimal hyperplasia (IH) and accelerated atherosclerosis, and these processes are thought to be inflammation driven, influx of monocytes is one of the first phenomena seen in IH, we would like to provide direct evidence for a role of the MCP-1 pathway in the development of vein graft disease. METHODS AND RESULTS - MCP-1 expression is demonstrated in various stages of vein graft disease in a murine model in which venous interpositions are placed in the carotid arteries of hypercholesterolemic ApoE3Leiden mice and in cultured human saphenous vein (HSV) segments in which IH occurs. The functional involvement of MCP-1 in vein graft remodeling is demonstrated by blocking the MCP-1 receptor CCR-2 using 7ND-MCP-1. 7ND-MCP1 gene transfer resulted in 51% reduction in IH in the mouse model, when compared with controls. In HSV cultures neointima formation was inhibited by 53%. In addition, we demonstrate a direct inhibitory effect of 7ND-MCP-1 on the proliferation of smooth muscle cell (SMC) in HSV cultures and in SMC cell cultures. CONCLUSION - These data, for the first time, prove that MCP-1 has a pivotal role in vein graft thickening due to intimal hyperplasia and accelerated atherosclerosis. © 2006 American Heart Association, Inc. Chemicals / CAS: Ccl2 protein, mouse; Chemokine CCL2; monocyte chemoattractant protein 1 receptor, 156286-78-1; Receptors, Chemokine
Topics
Biomedical ResearchInflammationIntimal hyperplasiaMCP-1Smooth muscle cellsVein graft diseaseApolipoprotein EChemokine receptor CCR2Monocyte chemotactic protein 1Animal experimentAnimal modelAnimal tissueArtery intima proliferationAtherosclerosisCarotid arteryCell proliferationControlled studyGraft failureHumanHuman cellHuman tissueHypercholesterolemiaIn vitro studyIn vivo studyMonocyteMouseNonhumanProtein expressionSaphenous veinVascular smooth muscleVein graftAmino Acid SequenceAnimalsCarotid ArteriesCell ProliferationCells, CulturedChemokine CCL2Gene TherapyHumansHypercholesterolemiaMaleMiceMice, Inbred C57BLMuscle, Smooth, VascularMyocytes, Smooth MuscleOrgan Culture TechniquesReceptors, ChemokineSaphenous VeinSequence DeletionTunica Intima
TNO Identifier
239462
ISSN
10795642
Source
Arteriosclerosis, Thrombosis, and Vascular Biology, 26(9), pp. 2063-2069.
Pages
2063-2069
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