title: Lack of mitogen-activated protein kinase phosphatase-1 protects ApoE-null mice against atherosclerosis.
abstract: BACKGROUND
  Multiple protein kinases have been implicated in cardiovascular disease; however, little is known about the role of their counterparts: the protein phosphatases.
  
  
  OBJECTIVE
  To test the hypothesis that mitogen-activated protein kinase phosphatase (MKP)-1 is actively involved in atherogenesis.
  
  
  RESULTS
  Mice with homozygous deficiency in MKP-1 (MKP-1(-/-)) were bred with apolipoprotein (Apo)E-deficient mice (ApoE(-/-)) and the 3 MKP-1 genotypes (MKP-1(+/+)/ApoE(-/-) ; MKP-1(+/-)/ApoE(-/-) and MKP-1(-/-)/ApoE(-/-)) were maintained on a normal chow diet for 16 weeks. The 3 groups of mice exhibited similar body weight and serum lipid profiles; however, both MKP-1(+/-) and MKP-1(-/-) mice had significantly less aortic root atherosclerotic lesion formation than MKP-1(+/+) mice. Less en face lesion was observed in 8-month-old MKP-1(-/-) mice. The reduction in atherosclerosis was accompanied by decreased plasma levels of interleukin-1alpha and tumor necrosis factor alpha, and preceded by increased antiinflammatory cytokine interleukin-10. In addition, MKP-1-null mice had higher levels of plasma stromal cell-derived factor-1a, which negatively correlated with atherosclerotic lesion size. Immunohistochemical analysis revealed that MKP-1 expression was enriched in macrophage-rich areas versus smooth muscle cell regions of the atheroma. Furthermore, macrophages isolated from MKP-1-null mice showed dramatic defects in their spreading/migration and impairment in extracellular signal-regulated kinase, but not c-Jun N-terminal kinase and p38, pathway activation. In line with this, MKP-1-null atheroma exhibited less macrophage content. Finally, transplantation of MKP-1-intact bone marrow into MKP-1-null mice fully rescued the wild-type atherosclerotic phenotype.
  
  
  CONCLUSIONS
  These findings demonstrate that chronic deficiency of MKP-1 leads to decreased atherosclerosis via mechanisms involving impaired macrophage migration and defective extracellular signal-regulated kinase signaling.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio 44195, USA. JZS0019@auburn.edu
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Shen
authors.forename: Unni M
authors.initials: UM
authors.lastname: Chandrasekharan
authors.forename: Mohammad Z
authors.initials: MZ
authors.lastname: Ashraf
authors.forename: Eric
authors.initials: E
authors.lastname: Long
authors.forename: Richard E
authors.initials: RE
authors.lastname: Morton
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Paul E
authors.initials: PE
authors.lastname: DiCorleto
mesh_terms: D000375:Aging; D000818:Animals; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000097:blood; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005838:Genotype; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D053582:Interleukin-1alpha / Q000097:blood; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D018836:Inflammation Mediators; D053582:Interleukin-1alpha; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse