Atherosclerosis is a chronic inflammatory disease in which macrophages infiltrate the arterial wall, releasing myeloperoxidase (MPO), an oxidant-generating enzyme. Oxidation of LDL increases its uptake by macrophages to create lipid laden foam cells. The efflux of cholesterol from foam cells is impaired by MPO oxidation of apoA1, resulting in dysfunctional HDL. MPO expression is governed in part by a functional promoter polymorphism, -463G/A, which alters expression levels, and is associated with increased atherosclerosis, serum cholesterol, triglycerides and weight gain/obesity, both in human studies and in mouse models of atherosclerosis. The -463G/A polymorphism is situated in an Alu, within a cluster of nuclear receptor binding sites, including sites for PPAR?, estrogen receptor, and LXR. PPAR? strongly induces human MPO expression in macrophages, while estrogen receptor binds an overlapping site, blocking PPAR? binding and activity. LXR binds the middle site and downregulates human MPO gene expression in cultured macrophages. Mouse models are an important tool by which to investigate the regulation of MPO in vivo, and its effects on atherosclerosis. However, the mouse MPO gene is not expressed in lesions, therefore existing models cannot be used to study the role of MPO. To circumvent this problem, we generated transgenic mice expressing the human MPO gene, and crossed these to the LDLR-/- model for atherosclerosis. On a high fat Western diet, these transgenics developed larger lesions, increased serum cholesterol, triglycerides, and glucose, correlating with excessive weight gain/obesity. Here we propose to use these human MPO transgenics to determine if PPAR?, estrogen receptor, or LXR regulate human MPO gene expression in vivo in atherosclerosis lesions, and determine if such regulation impacts the development of atherosclerosis or hyperlipidemia.
Aim 1 is an investigation of the effects of PPAR? and estrogen receptor on MPO expression and its effects.
Aim 2 examines the effects of LXR, a key modulator of lipid metabolism, on MPO expression and its effects. A subaim will investigate the effects of statins, atheroprotective agents which downregulate MPO expression in macrophages. ? ? ?
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