Antimonocyte chemoattractant protein-1 gene therapy attenuates graft vasculopathy.

Abstract

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.

• Authors: Akio Saiura, Masataka Sata, Ken-ichi Hiasa, Shiro Kitamoto, Miwa Washida, Kensuke Egashira, Ryozo Nagai, Masatoshi Makuuchi
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 24 Issue 10 Pg. 1886-90 (Oct 2004) ISSN: 1524-4636 [Electronic] United States
• PMID: 15284091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccr2 protein, mouse
• Chemokine CCL2
• Receptors, CCR2
• Receptors, Chemokine

Topics

• Animals
• Arteriosclerosis (prevention & control)
• Chemokine CCL2 (biosynthesis, genetics)
• Coronary Vessels (physiology)
• Disease Models, Animal
• Gene Transfer Techniques
• Genes, Dominant (physiology)
• Genetic Therapy (methods)
• Heart Transplantation (methods)
• Hyperplasia (prevention & control)
• Inflammation (genetics, pathology)
• Leukocytes, Mononuclear (metabolism)
• Male
• Mice
• Mice, Inbred DBA
• Mice, Inbred Strains
• Muscle, Skeletal (chemistry, metabolism)
• Receptors, CCR2
• Receptors, Chemokine (metabolism)
• Signal Transduction (genetics)
• Transplantation, Heterotopic
• Transplantation, Homologous
• Tunica Intima (pathology)