title: Deficiency of glutathione peroxidase-1 accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice.
abstract: BACKGROUND
  We have recently demonstrated that activity of red blood cell glutathione peroxidase-1 is inversely associated with the risk of cardiovascular events in patients with coronary artery disease. The present study analyzed the effect of glutathione peroxidase-1 deficiency on atherogenesis in the apolipoprotein E-deficient mouse.
  
  
  RESULTS
  Female apolipoprotein E-deficient mice with and without glutathione peroxidase-1 deficiency were placed on a Western-type diet for another 6, 12, or 24 weeks. After 24 weeks on Western-type diet, double-knockout mice (GPx-1(-/-)ApoE(-/-)) developed significantly more atherosclerosis than control apolipoprotein E-deficient mice. Moreover, glutathione peroxidase-1 deficiency led to modified atherosclerotic lesions with increased cellularity. Functional experiments revealed that glutathione peroxidase-1 deficiency leads to increased reactive oxygen species concentration in the aortic wall as well as increased overall oxidative stress. Peritoneal macrophages from double-knockout mice showed increased in vitro proliferation in response to macrophage-colony-stimulating factor. Also, we found lower levels of bioactive nitric oxide as well as increased tyrosine nitration as a marker of peroxynitrite production.
  
  
  CONCLUSIONS
  Deficiency of an antioxidative enzyme accelerates and modifies atherosclerotic lesion progression in apolipoprotein E-deficient mice.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University, 55101 Mainz, Germany. torzewski@zentrallabor.klinik.uni-mainz.de
authors.forename: Michael
authors.initials: M
authors.lastname: Torzewski
authors.forename: Viola
authors.initials: V
authors.lastname: Ochsenhirt
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Kleschyov
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Huige
authors.initials: H
authors.lastname: Li
authors.forename: Heidi
authors.initials: H
authors.lastname: Rossmann
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.forename: Kurt
authors.initials: K
authors.lastname: Reifenberg
authors.forename: Fei
authors.initials: F
authors.lastname: Cheng
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.forename: Ulrich
authors.initials: U
authors.lastname: Förstermann
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Lackner
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency*; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D001794:Blood Pressure; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D005979:Glutathione Peroxidase / Q000172:deficiency*; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D008566:Membranes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D009000:Monocytes / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D001057:Apolipoproteins E; D008074:Lipoproteins; D017382:Reactive Oxygen Species; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse