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A Human Ex Vivo Atherosclerotic Plaque Model to Study Lesion Biology
Published on: May 6, 2014
Expression of human myeloperoxidase by macrophages promotes atherosclerosis in mice
Timothy S McMillen1, Jay W Heinecke, Renee C LeBoeuf
1Department of Medicine, University of Washington, Seattle, WA 98109-8050, USA.
Background:
Myeloperoxidase (MPO) colocalizes with macrophages in the human artery wall, and its characteristic oxidation products have been detected in atherosclerotic lesions. Thus, oxidants produced by the enzyme might promote atherosclerosis. However, macrophages in mouse atherosclerotic tissue do not express MPO. Therefore, mice are an inappropriate model for testing the role of MPO in vascular disease. To overcome this problem, we generated and studied transgenic (Tg) mice that contained the human MPO gene.
Methods And Results:
We produced human MPO-Tg mice with use of a Visna virus promoter. To confine MPO expression to macrophages, we lethally irradiated LDL receptor-deficient mice and repopulated their bone marrow with cells from wild-type mice or MPO-Tg mice. Despite having similarly high levels of cholesterol after maintenance on a high-fat, high-cholesterol diet, the MPO-Tg animals developed a 2-fold greater atherosclerotic area in the aorta than did mice transplanted with wild-type bone marrow (P=0.00003).
Conclusions:
Our observations indicate that expression of human MPO in macrophages promotes atherosclerosis in hypercholesterolemic mice, raising the possibility that the enzyme might be a potential therapeutic target for preventing cardiovascular disease in humans.
Insights
Transgenic mice expressing human myeloperoxidase (MPO) in macrophages showed a twofold increase in atherosclerosis. This suggests MPO may be a therapeutic target for cardiovascular disease.
Area of Science:
- Cardiovascular Science
- Immunology
- Genetics
Background:
- Myeloperoxidase (MPO) is present in human artery walls and associated with atherosclerosis.
- Macrophages in mouse models do not express MPO, limiting their utility.
- Human MPO gene was introduced into mice to study its role in vascular disease.
Purpose of the Study:
- To investigate the role of macrophage-expressed MPO in the development of atherosclerosis.
- To create a mouse model for studying MPO's contribution to vascular disease.
Main Methods:
- Generated transgenic (Tg) mice expressing the human MPO gene.
- Used bone marrow transplantation to ensure MPO expression was confined to macrophages.
- Utilized LDL receptor-deficient mice on a high-fat, high-cholesterol diet.
Main Results:
- MPO-Tg mice exhibited a twofold increase in aortic atherosclerotic area compared to controls.
- High cholesterol levels were comparable between MPO-Tg and wild-type bone marrow recipients.
- The study established a link between MPO expression in macrophages and atherosclerosis progression.
Conclusions:
- Macrophage expression of human MPO significantly promotes atherosclerosis in hypercholesterolemic mice.
- MPO emerges as a potential therapeutic target for cardiovascular disease prevention in humans.
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