title: Mitogen-activated protein kinase phosphatase-1 deficiency decreases atherosclerosis in apolipoprotein E null mice by reducing monocyte chemoattractant protein-1 levels.
abstract: BACKGROUND
  We previously reported that mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is necessary for oxidized phospholipids to induce monocyte chemoattractant protein-1 (MCP-1) secretion by human aortic endothelial cells. We also reported that inhibition of tyrosine phosphatases including MKP-1 ameliorated atherosclerotic lesions in mouse models of atherosclerosis.
  
  
  OBJECTIVE
  This study was conducted to further investigate the specific role of MKP-1 in atherogenesis.
  
  
  RESULTS
  We generated MKP-1(-/-)/apoE(-/-) double-knockout mice. At 24weeks of age, the size, macrophage and dendritic cell content of atherosclerotic lesions of the aortic root were significantly lower ( approximately -41% for lesions and macrophages, and approximately -78% for dendritic cells) in MKP-1(-/-)/apoE(-/-) mice when compared with apoE(-/-) mice. Total cholesterol (-18.4%, p=0.045) and very low-density lipoprotein (VLDL)/low-density lipoprotein (LDL) cholesterol (-20.0%, p=0.052) levels were decreased in MKP-1(-/-)/apoE(-/-) mice. Serum from MKP-1(-/-)/apoE(-/-) mice contained significantly lower levels of MCP-1 and possessed significantly reduced capability to induce monocyte migration in vitro. Moreover, peritoneal macrophages isolated from MKP-1(-/-)/apoE(-/-) mice produced significantly lower levels of MCP-1 when compared to peritoneal macrophages from apoE(-/-) mice. Furthermore, MKP-1(-/-)/apoE(-/-) mice had significantly reduced serum hydroxyeicosatetraenoic acids (HETEs) levels, which have been reported to induce MCP-1 levels.
  
  
  CONCLUSIONS
  Our results demonstrate that MKP-1 deficiency significantly decreases atherosclerotic lesion development in mice, in part, by affecting MCP-1 levels in the circulation and MCP-1 production by macrophages. MKP-1 may serve as a potential therapeutic target for the treatment of atherosclerotic disease.
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, CA 90095-1679, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imaizumi
authors.forename: Victor
authors.initials: V
authors.lastname: Grijalva
authors.forename: Saul
authors.initials: S
authors.lastname: Priceman
authors.forename: Lily
authors.initials: L
authors.lastname: Wu
authors.forename: Feng
authors.initials: F
authors.lastname: Su
authors.forename: Robin
authors.initials: R
authors.lastname: Farias-Eisner
authors.forename: Susan
authors.initials: S
authors.lastname: Hama
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E; D018932:Chemokine CCL2; D006893:Hydroxyeicosatetraenoic Acids; D054638:Dual Specificity Phosphatase 1