New anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice.
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.


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.
Ni
W
W
Department of Cardiovascular Medicine, Kyushu University, Fukuoka, Japan.
Egashira
K
K
Kitamoto
S
S
Kataoka
C
C
Koyanagi
M
M
Inoue
S
S
Imaizumi
K
K
Akiyama
C
C
Nishida
K I
KI
Takeshita
A
A
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics / Q000628:therapy*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007958:Leukocyte Count; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D017384:Sequence Deletion; D012867:Skin / Q000166:cytology / Q000187:drug effects; D014162:Transfection; D016896:Treatment Outcome
D001057:Apolipoproteins E; D018932:Chemokine CCL2; D008055:Lipids; D010446:Peptide Fragments; D011994:Recombinant Proteins