Increased atherosclerosis in myeloperoxidase-deficient mice

M Brennan

M Anderson

D Shih

X Qu

S Hazen+4 authors

^{Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, California, USA}^{Departments of Medicine and Molecular Biology and Pharmacology, Washington University, St. Louis, Missouri, USA}^{Department of Medicine, UCLA, Los Angeles, California, USA}^{Departments of Cardiology and Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio, USA}^{Department of Human Genetics, UCLA, Los Angeles, California, USA}

Address correspondence to: Aldons J. Lusis, UCLA, Department of Medicine, 47-123 Center for Health Sciences, Los Angeles, California 90095-1679, USA. Phone: (310) 825-1359; Fax: (310) 794-7345; E-mail: ude.alcu.tendem@sisulj.

Received 1999 Oct 28; Accepted 2001 Jan 9.

Abstract

Myeloperoxidase (MPO), a heme enzyme secreted by activated phagocytes, generates an array of oxidants proposed to play critical roles in host defense and local tissue damage. Both MPO and its reaction products are present in human atherosclerotic plaque, and it has been proposed that MPO oxidatively modifies targets in the artery wall. We have now generated MPO-deficient mice, and show here that neutrophils from homozygous mutants lack peroxidase and chlorination activity in vitro and fail to generate chlorotyrosine or to kill Candida albicans in vivo. To examine the potential role of MPO in atherosclerosis, we subjected LDL receptor–deficient mice to lethal irradiation, repopulated their marrow with MPO-deficient or wild-type cells, and provided them a high-fat, high-cholesterol diet for 14 weeks. White cell counts and plasma lipoprotein profiles were similar between the two groups at sacrifice. Cross-sectional analysis of the aorta indicated that lesions in MPO-deficient mice were about 50% larger than controls. Similar results were obtained in a genetic cross with LDL receptor–deficient mice. In contrast to advanced human atherosclerotic lesions, the chlorotyrosine content of aortic lesions from wild-type as well as MPO-deficient mice was essentially undetectable. These data suggest an unexpected, protective role for MPO-generated reactive intermediates in murine atherosclerosis. They also identify an important distinction between murine and human atherosclerosis with regard to the potential involvement of MPO in protein oxidation.

Abstract

Acknowledgments

We thank H. Cheroutre and K. Williams (UCLA Transgenic Core Facility) for blastocyst injections, K.M. Lyons (UCLA) for advice on gene targeting, and L. Castellani and S. Charugundula (UCLA) for lipoprotein analyses. We are grateful to R.I. Lehrer (UCLA) for helpful discussions and guidance. We thank T. McMillan and R. LeBoeuf (University of Washington, Seattle, Washington, USA) and W. Nauseef (The University of Iowa, Iowa City, Iowa, USA) for providing Ab samples. We thank the Washington University Mass Spectrometry Resource for mass spectrometry analyses. Development and maintenance of MPO-deficient mice, host defense experiments, and atherosclerosis studies were funded by NIH grant HL30568 (A.J. Lusis). Chlorination analyses and Western blot analysis were funded by NIH grants AG-08487, AG-12293, AG-15013, DK-02456, and RR-00954 and by the Monsanto-Searle/Washington University Biomedical Program (J.W. Heinecke).

Acknowledgments

Footnotes

Marie-Luise Brennan’s present address is: Cleveland Clinic Foundation, Department of Cell Biology, Cleveland, Ohio, USAHost defense phenotype presented in oral and abstract form at the Peroxidase Multigene Family of Enzymes: Biochemical Basis and Clinical Applications Meeting, Chiemgau, Germany, September 1998.

Footnotes

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