Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in rats: blockade of MCP-1 activity after intramuscular transfer ofa mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis

Monocyte chemoattractant protein-1 (MCP-1) may play an essential part in th e formation of arteriosclerosis by recruiting monocytes into the arterial w all. Thus, we devised a new strategy for anti-MCP-1 gene therapy against ar teriosclerosis by transfecting an amino-terminal deletion mutant (missing t he amino-terminal amino acids 2 to 8) of the human MCP-1 gene into a remote organ (skeletal muscles), Intramuscular transduction with the mutant MCP-1 gene blocked monocyte recruitment induced by a subcutaneous injection of r ecombinant MCP-1. In a rat model in which the chronic inhibition of endothe lial nitric oxide synthesis induces early vascular inflammation as well as subsequent coronary vascular remodeling, this strategy suppressed monocyte recruitment into the coronary vessels and the development of vascular media l thickening, but did not reduce perivascular fibrosis. Thus, MCP-1 is nece ssary far the development of medial thickening but not for fibrosis in this model. This new strategy may be a useful and feasible gene therapy against arteriosclerosis.