Deficiency of glutathione peroxidase-1 accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice.
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.
Torzewski
Michael
M
Institute of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University, 55101 Mainz, Germany. torzewski@zentrallabor.klinik.uni-mainz.de
Ochsenhirt
Viola
V
Kleschyov
Andrei L
AL
Oelze
Matthias
M
Daiber
Andreas
A
Li
Huige
H
Rossmann
Heidi
H
Tsimikas
Sotirios
S
Reifenberg
Kurt
K
Cheng
Fei
F
Lehr
Hans-Anton
HA
Blankenberg
Stefan
S
Förstermann
Ulrich
U
Münzel
Thomas
T
Lackner
Karl J
KJ
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
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