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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1886.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Antimonocyte Chemoattractant Protein-1 Gene Therapy Attenuates Graft Vasculopathy

Akio Saiura; Masataka Sata; Ken-ichi Hiasa; Shiro Kitamoto; Miwa Washida; Kensuke Egashira; Ryozo Nagai; Masatoshi Makuuchi

From the Departments of Surgery (A.S., M.M.) and Cardiovascular Medicine (M.S., M.W., R.N.), University of Tokyo, Graduate School of Medicine, Japan; and the Department of Cardiovascular Medicine (K.H., S.K., K.E.), University of Kyushu, Graduate School of Medicine, Fukuoka, Japan.

Correspondence to Dr Masataka Sata, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: msata-tky{at}umin.ac.jp

Objective— Accelerated coronary arteriosclerosis remains a major problem in the long-term survival of cardiac transplant recipients. However, the pathogenesis of graft vasculopathy is poorly understood, and there is no effective therapy. Transplant arteriosclerosis is characterized by early mononuclear cell attachment on the transplanted vessel followed by development of concentric neointimal hyperplasia. Early and persistent expression of monocyte chemoattractant protein-1 (MCP-1) in cardiac allografts has been implicated for the pathogenesis of transplant arteriosclerosis.

Methods and Results— We investigated whether anti-MCP-1 gene therapy can inhibit the development of intima hyperplasia in a mouse model of cardiac transplantation. Either the dominant-negative form of MCP-1 (7ND) or control vector was transfected into the skeletal muscles of B10.D2 mice. Cardiac allografts from DBA/2 mice were transplanted heterotopically into B10.D2 mice. 7ND gene transfer was associated with a significant reduction of the number of mononuclear cells accumulating in the lumen of the graft coronary arteries at 1 week and an attenuation of the development of the lesion at 8 weeks (intima/media ratio 0.79±0.05 versus 0.48±0.04).

Conclusions— The MCP-1/chemokine receptor 2 (CCR2) signaling pathway plays a critical role in the pathogenesis of graft vasculopathy. This new anti-MCP-1 gene therapy might be useful to treat graft vascular disease.

In a murine cardiac allograft model, the gene transfer of the dominant negative form of MCP-1 to the recipients significantly reduced the number of mononuclear cells accumulating in the luminal side of the graft coronary arteries at 1 week and attenuated the development of the lesion at 8 weeks.

Key Words: cardiac transplantation • graft arteriosclerosis • MCP-1 • CCR2 • chemokine

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