Transgenic mice express human MPO −463G/A alleles at atherosclerotic lesions, developing hyperlipidemia and obesity in −463G males

Abstract

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 2463, and crossed these to the LDL receptor-deficient (LDLR 2/2 ) mouse. The 2463G 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 2/2 mice, notably at necrotic lesions with cholesterol clefts. MPOGexpressing LDLR 2/2 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 2/2 males also exhibited significantly larger aortic lesions than control LDLR 2/2 males. The human MPO transgenic model will facilitate studies of MPO involvement in atherosclerosis and lipid homeostasis.-Castellani, L. W., J. J. Chang, X. Wang, A. J. Lusis, and W. F. Reynolds. Transgenic mice express human MPO 2463G/A alleles at athrosclerotic lesions, developing hyperlipidemia and obesity in 2463G males. J. Lipid Res. 2006.

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

“…Repopulating the bone marrow of LDLr -/-mice with bone marrow from transgenic mice expressing human myeloperoxidase resulted in increased atherosclerosis (57). Another study, utilizing the overexpression of different human MPO allele polymorphisms in the promoter region, likewise demonstrated increased aortic lesions in male mice only, thus highlighting the role of estrogen in ameliorating MPO expression (77). Yet MPO polymorphism and its effect on MPO expression are much more complicated (78): while some studies implicate the GG phenotype with an increased risk of CVD (72,78), other studies have not clearly replicated this finding (79,80).…”

“…Repopulating the bone marrow of LDLr -/-mice with bone marrow from transgenic mice expressing human myeloperoxidase resulted in increased atherosclerosis (57). Another study, utilizing the overexpression of different human MPO allele polymorphisms in the promoter region, likewise demonstrated increased aortic lesions in male mice only, thus highlighting the role of estrogen in ameliorating MPO expression (77 (79,80). Our model of CKD atherosclerosis is the first of its kind to demonstrate marked upregulation of mouse MPO and its specific oxidation products in response to reduced renal function and HFD in murine atherosclerosis.…”

The human myeloperoxidase gene is regulated by LXR and PPARα ligands

“…In a previous study, these huMPO transgenic mice were crossed onto the LDLR−/ − background and fed a high fat Western diet, resulting in larger atherosclerosis lesions, as well as hypercholesterolemia, hypertriglycerolemia, and obesity in males [38]. Considering the central role of LXR and PPARα in regulation of genes involved in lipid metabolism [32,33,36], we investigated the ability of these receptors to regulate MPO gene expression.…”

Interindividual variability of atorvastatin treatment influence on the MPO gene expression in patients after acute myocardial infarction.

“…Several genetic polymorphisms in the MPO gene were described (Wainstein et al, 2010;Scharnagi et al, 2014;Nikpoor et al, 2001). Some studies suggest that MPO polymorphism in the promoter region (-463G/A) might be associated with coronary artery disease (Castellani et al, 2006;Reynolds et al, 2006;Yang et al, 2013). However, this preliminary hypothesis still requires detailed studies.…”