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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:850.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Deficiency of Glutathione Peroxidase-1 Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice

Michael Torzewski; Viola Ochsenhirt; Andrei L. Kleschyov; Matthias Oelze; Andreas Daiber; Huige Li; Heidi Rossmann; Sotirios Tsimikas; Kurt Reifenberg; Fei Cheng; Hans-Anton Lehr; Stefan Blankenberg; Ulrich Förstermann; Thomas Münzel; Karl J. Lackner

From the Institute of Clinical Chemistry and Laboratory Medicine (M.T., V.O., F.C., H.R., K.J.L.), Department of Medicine II (A.L.K., M.O., A.D., S.B., T.M.), Department of Pharmacology (H.L., U.F.), Central Laboratory Animal Facility (K.R.), Johannes Gutenberg University, Mainz, Germany; Division of Cardiology (S.T), University of California, San Diego, Calif; Institute Universitaire de Pathologie (H-A.L.), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

Correspondence to Michael Torzewski, MD, or to Karl J. Lackner, MD, Institute of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University, 55101 Mainz, Germany. E-mail torzewski{at}zentrallabor.klinik.uni-mainz.de or lackner@zentrallabor.klinik.uni-mainz.de

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.

Methods and 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.

The present study analyzed the effect of glutathione peroxidase-1 (GPx-1) deficiency on atherogenesis in the apolipoprotein E-deficient mouse (ApoE^–/–) on the C57BL/6J background. Our data demonstrate that deficiency of an antioxidative enzyme accelerates and modifies atherosclerotic lesion progression in ApoE^–/– mice.

Key Words: antioxidants • atherosclerosis • nitric oxide

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