on July 6, 2006
Published online before print July 6, 2006, doi: 10.1161/01.ATV.0000235694.69719.e2
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Submitted on July 4, 2005
Accepted on June 2, 2006
Anti-MCP-1 Gene Therapy Inhibits Vascular Smooth Muscle Cells Proliferation and Attenuates Vein Graft Thickening Both In Vitro and In Vivo
A. Schepers ;
From the Gaubius Laboratory TNO-Quality of Life (A.S., D.E., J.M.G., M.R.d.V., V.v.W., P.H.A.Q.), Leiden; the Department of Vascular Surgery (A.S., D.E., V.v.W., J.H.v.B., P.H.A.Q.), Leiden University Medical Centre, Leiden; and the Department of Medical Biochemistry (P.I.B., C.J.d.V.), Academic Medical Center, Amsterdam, The Netherlands; and the Graduate School of Medical Sciences (K.E.), Kyushu University, Fukuoka, Japan.
* To whom correspondence should be addressed. E-mail: pha.quax{at}pg.tno.nl.
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.
Key words: vein graft disease • intimal hyperplasia • MCP-1 • smooth muscle cells • inflammation
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