Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in rats: blockade of MCP-1 activity after intramuscular transfer of a mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis.
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.
Egashira
K
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. egashira@cardiol.med.kyushu-u.ac.jp
Koyanagi
M
M
Kitamoto
S
S
Ni
W
W
Kataoka
C
C
Morishita
R
R
Kaneda
Y
Y
Akiyama
C
C
Nishida
K I
KI
Sueishi
K
K
Takeshita
A
A
D000818:Animals; D001161:Arteriosclerosis / Q000628:therapy*; D018932:Chemokine CCL2 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000235:genetics; D002634:Chemotaxis, Leukocyte; D003331:Coronary Vessels / Q000187:drug effects; D020405:Dermis; D015316:Genetic Therapy / Q000379:methods*; D007273:Injections, Intramuscular; D008297:Male; D009000:Monocytes / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D011921:Rats, Inbred WKY; D011994:Recombinant Proteins / Q000008:administration & dosage
D018932:Chemokine CCL2; D011994:Recombinant Proteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat