Submitted on January 6, 2006
Revised on April 25, 2006
Accepted on April 25, 2006
Transgenic mice express human MPO -463G/A alleles at atherosclerotic lesions, developing hyperlipidemia and obesity in -463G males
Lawrence W. Castellani, James J. Chang, Xuping Wang, Aldons J. Lusis, and Wanda F. Reynolds
Molecular Biology, Sidney Kimmel Cancer Center, San Diego, Ca 92121
Corresponding Author: wreynolds{at}skcc.org
Myeloperoxidase (MPO) is an oxidant-generating enzyme present in macrophages at atherosclerotic lesions and implicated in cardiovascular disease (CAD). While mouse models are important for investigating the role of MPO in atherosclerosis, neither mouse MPO nor its oxidation products are detected in lesions in murine models. To circumvent this problem, we generated transgenic mice expressing two functionally different human MPO alleles, with either G or an A at position –463, and crossed these to the LDLR-/- mouse. The –463G allele is linked to higher MPO expression and increased CAD incidence in humans. Both MPO alleles were expressed in a subset of lesions in high fat-fed LDLR-/- mice, notably at necrotic lesions with cholesterol clefts. MPOG-expressing LDLR-/- males (but not females) developed significantly higher serum cholesterol, triglycerides, and glucose, all correlating with increased weight gain/obesity, implicating MPO in lipid homeostasis. The MPOG- and A-LDLR-/- males also exhibited significantly larger aortic lesions than control LDLR-/- males. The human MPO transgenic model will facilitate studies of MPO involvement in atherosclerosis and lipid homeostasis.
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