ABSTRACT
BACKGROUND: Monocyte recruitment into the arterial wall and its activation may be the central event in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine for monocyte recruitment, and its receptor (CCR2) may mediate such in vivo response. Although the importance of the MCP-1/CCR2 pathway in atherogenesis has been clarified, it remains unanswered whether postnatal blockade of the MCP-1 signals could be a unique site-specific gene therapy. METHODS AND RESULTS: We devised a new strategy for anti-MCP-1 gene therapy to treat atherosclerosis by transfecting an N-terminal deletion mutant of the human MCP-1 gene into a remote organ (skeletal muscle) in apolipoprotein E-knockout mice. This strategy effectively blocked MCP-1 activity and inhibited the formation of atherosclerotic lesions but had no effect on serum lipid concentrations. Furthermore, this strategy increased the lesional extracellular matrix content. CONCLUSIONS: We conclude that this anti-MCP-1 gene therapy may serve not only to reduce atherogenesis but also to stabilize vulnerable atheromatous plaques. This strategy may be a useful and feasible form of gene therapy against atherosclerosis in humans.
Subject(s)
Apolipoproteins E/deficiency , Arteriosclerosis/therapy , Chemokine CCL2/antagonists & inhibitors , Genetic Therapy/methods , Peptide Fragments/pharmacology , Animals , Aorta/drug effects , Aorta/pathology , Apolipoproteins E/genetics , Arteriosclerosis/genetics , Chemokine CCL2/genetics , Chemokine CCL2/pharmacology , Chemotaxis/drug effects , Disease Models, Animal , Disease Progression , Humans , Leukocyte Count , Lipids/blood , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/cytology , Monocytes/drug effects , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Peptide Fragments/genetics , Recombinant Proteins/pharmacology , Sequence Deletion , Skin/cytology , Skin/drug effects , Transfection , Treatment OutcomeABSTRACT
Monocyte chemoattractant protein-1 (MCP-1) may play an essential part in the formation of arteriosclerosis by recruiting monocytes into the arterial wall. Thus, we devised a new strategy for anti-MCP-1 gene therapy against arteriosclerosis by transfecting an amino-terminal deletion mutant (missing the 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 recombinant MCP-1. In a rat model in which the chronic inhibition of endothelial 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 medial thickening, but did not reduce perivascular fibrosis. Thus, MCP-1 is necessary for 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.
