title: Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein E-knockout mice.
abstract: BACKGROUND
  Monocyte infiltration into the arterial wall and its activation is the central event in atherogenesis. Thus, monocyte chemoattractant protein-1 (MCP-1) might be a novel therapeutic target against atherogenesis. We and others recently reported that blockade or abrogation of the MCP-1 pathway attenuates the initiation of atheroma formation in hypercholesterolemic mice. It remains unclear, however, whether blockade of MCP-1 can limit progression or destabilization of established lesions.
  
  
  RESULTS
  We report here that blockade of MCP-1 by transfecting an N-terminal deletion mutant of the MCP-1 gene limited progression of preexisting atherosclerotic lesions in the aortic root in hypercholesterolemic mice. In addition, blockade of MCP-1 changed the lesion composition into a more stable phenotype, ie, containing fewer macrophages and lymphocytes, less lipid, and more smooth muscle cells and collagen. This strategy decreased expression of CD40 and the CD40 ligand in the atherosclerotic plaque and normalized the increased chemokine (RANTES and MCP-1) and cytokine (tumor necrosis factor alpha, interleukin-6, interleukin-1beta, and transforming growth factor beta(1)) gene expression. These data suggest that MCP-1 is a central mediator in the progression and destabilization of established atheroma.
  
  
  CONCLUSIONS
  The results of the present study suggest that the inflammatory responses mediated by MCP-1 are important in atherosclerosis and its complications.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shujiro
authors.initials: S
authors.lastname: Inoue
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Weihua
authors.initials: W
authors.lastname: Ni
authors.forename: Shiro
authors.initials: S
authors.lastname: Kitamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Usui
authors.forename: Kisho
authors.initials: K
authors.lastname: Otani
authors.forename: Minako
authors.initials: M
authors.lastname: Ishibashi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hiasa
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Nishida
authors.forename: Akira
authors.initials: A
authors.lastname: Takeshita
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006937:Hypercholesterolemia / Q000235:genetics; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013601:T-Lymphocytes / Q000473:pathology; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D019013:CD40 Antigens; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D010446:Peptide Fragments; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D023201:CD40 Ligand; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020780:Matrix Metalloproteinase 9