Castellani Lawrence W, Chang James J, Wang Xuping, Lusis Aldons J, Reynolds Wanda F
Department of Medicine, University of California-Los Angeles, 90095, USA.
J Lipid Res. 2006 Jul;47(7):1366-77. doi: 10.1194/jlr.M600005-JLR200. Epub 2006 Apr 25.
Myeloperoxidase (MPO) is an oxidant-generating enzyme present in macrophages at atherosclerotic lesions and implicated in coronary artery disease (CAD). Although 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 A at position -463, and crossed these to the LDL receptor-deficient (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 MPOA-expressing 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.
髓过氧化物酶（MPO）是一种产生氧化剂的酶，存在于动脉粥样硬化病变处的巨噬细胞中，并与冠状动脉疾病（CAD）有关。尽管小鼠模型对于研究MPO在动脉粥样硬化中的作用很重要，但在小鼠模型的病变中未检测到小鼠MPO及其氧化产物。为了解决这个问题，我们构建了表达两种功能不同的人类MPO等位基因的转基因小鼠，其-463位分别为G或A，并将这些小鼠与低密度脂蛋白受体缺陷（LDLR(-/-)）小鼠杂交。-463G等位基因与人类中较高的MPO表达和增加的CAD发病率相关。两种MPO等位基因在高脂喂养的LDLR(-/-)小鼠的一部分病变中表达，特别是在有胆固醇裂隙的坏死病变处。表达MPOG的LDLR(-/-)雄性小鼠（而非雌性小鼠）的血清胆固醇、甘油三酯和葡萄糖显著升高，所有这些都与体重增加/肥胖增加相关，提示MPO参与脂质稳态。表达MPOG和MPOA的LDLR(-/-)雄性小鼠的主动脉病变也比对照LDLR(-/-)雄性小鼠明显更大。人类MPO转基因模型将有助于研究MPO在动脉粥样硬化和脂质稳态中的作用。
