Anti-MCP-1 gene therapy inhibits vascular smooth muscle cells proliferation and attenuates vein graft thickening both in vitro and in vivo.
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.


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.


CONCLUSIONS
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.
Schepers
A
A
Gaubius Laboratory, TNO-Quality of Life, Leiden, The Netherlands.
Eefting
D
D
Bonta
P I
PI
Grimbergen
J M
JM
de Vries
M R
MR
van Weel
V
V
de Vries
C J
CJ
Egashira
K
K
van Bockel
J H
JH
Quax
P H A
PH
D000595:Amino Acid Sequence; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D009924:Organ Culture Techniques; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000378:metabolism; D012501:Saphenous Vein / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation*; D017384:Sequence Deletion; D017539:Tunica Intima / Q000473:pathology
C515334:CCR2 protein, human; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine