Peroxiredoxin 6 deficiency and atherosclerosis susceptibility in mice:: significance of genetic background for assessing atherosclerosis

Peroxiredoxin 6 (Prdx6; also called antioxidant protein 2, or Aop2) is a candidate gene for Ath1, a locus responsible for the respective susceptibility and resistance of mouse strains C57BL/6J (136) and C3H/HeJ (C3H) to diet-induced atherosclerosis. To evaluate if Prdx6 underlies Ath1, we compared the diet-induced atherosclerotic lesions in Prdx6 targeted mutant (Prdx6(-/-)) mice of different genetic backgrounds: 136, 129, and B6;129. PRDX6 protein and mRNA were expressed in normal and atherosclerotic aortas. B6;129 Prdx6(-/-) macrophages oxidized LDL significantly more than did controls. Plasma lipid hydroperoxide levels were higher in atherogenic diet-fed Prdx6(-/-) mice with B6; 129 and 136 backgrounds than in controls. Prdx6(-/-) and controls in a 129 genetic background were equally lesion-resistant, and Prdx6(-/-) and controls in a 136 background were equally lesion-susceptible. In contrast, Prdx6(-/-) mice in a 136; 129 background had significantly larger aortic root lesions than did littermate wild type controls. Therefore, although PRDX6 protein did not affect atherosclerosis susceptibility in either the resistant 129 background or the susceptible 136 background, it may inhibit atherosclerosis in backgrounds with mixed pro- and anti-atherogenic genes. Thus, genetic background plays an important role in modulating atherogenesis in targeted mutant mice. However, we think it is unlikely that Prdx6 underlies Ath1. (C) 2004 Elsevier Ireland Ltd. All rights reserved.