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Published on: May 14, 2014
Neutrophil-derived myeloperoxidase promotes atherogenesis and neointima formation in mice
Vedat Tiyerili1, Bakary Camara1, Marc U Becher1
1Department of Cardiology, University of Bonn, Bonn, Germany.
Background:
Myeloperoxidase (MPO), expressed mainly in neutrophils, is an enzyme linked to inflammation and oxidative stress. MPO is an independent prognostic marker in healthy individuals as well as in patients with coronary artery disease. In this present study we analyze the role of MPO in experimental atherogenesis and neointima formation after vascular injury in mice.
Methods And Results:
6-8 weeks old apolipoprotein E-deficient (ApoE(-/-)) mice were fed a high-cholesterol diet for 8 weeks with concomitant treatment with two different doses (10 μg/mg bw vs. 20 μg/mg bw) of 4-ABAH (MPO inhibitor). Application at lower dosage did not affect oxidative stress, endothelial function and atherosclerotic plaque development. 4-ABAH in higher dosage decreased inflammatory markers and vascular oxidative stress, consecutively improved endothelial function and reduced significantly atherosclerotic plaque development. To assess the role of circulating intracellular MPO, irradiated ApoE(-/-) mice were repopulated with bone marrow-derived cells from MPO(-/-) mice and were fed a high-cholesterol diet for 8 weeks. This MPO deficiency resulted in alleviated inflammation, reduced oxidative stress and improved endothelial function with a significant impact on plaque formation. To understand the possible role of MPO in vascular remodeling, we tested its effects on neointima formation following vascular injury in mice. MPO inhibition by 4-ABAH reduced significantly neointima formation. It was significantly reduced in MPO deficient mice, whereas transfer of spleen-derived neutrophils from WT mice enhanced it.
Conclusion:
Our data suggests a central role of MPO in the pathogenesis of atherogenesis and prefers pharmacological MPO inhibition as a therapeutic strategy for prevention and therapy of atherosclerosis and restenosis.
Insights
Myeloperoxidase (MPO) inhibition reduces inflammation and oxidative stress, significantly decreasing atherosclerotic plaque development and neointima formation. Pharmacological MPO inhibition is a promising therapeutic strategy for atherosclerosis and restenosis.
Area of Science:
- Cardiovascular Research
- Immunology
- Biochemistry
Background:
- Myeloperoxidase (MPO) is an enzyme primarily in neutrophils, linked to inflammation and oxidative stress.
- MPO serves as an independent prognostic marker in both healthy individuals and those with coronary artery disease.
- This study investigates MPO's role in experimental atherosclerosis and neointima formation post-vascular injury in mice.
Purpose of the Study:
- To analyze the role of myeloperoxidase (MPO) in experimental atherogenesis.
- To investigate MPO's involvement in neointima formation after vascular injury.
- To evaluate the therapeutic potential of MPO inhibition in atherosclerosis and restenosis.
Main Methods:
- Apolipoprotein E-deficient (ApoE(-/-)) mice on a high-cholesterol diet were treated with varying doses of the MPO inhibitor 4-ABAH.
- Irradiated ApoE(-/-) mice were repopulated with bone marrow from MPO-deficient (MPO(-/-)) mice.
- Mice underwent vascular injury to assess neointima formation, with MPO inhibition and deficiency models employed.
Main Results:
- High-dose 4-ABAH treatment significantly reduced inflammatory markers, vascular oxidative stress, improved endothelial function, and decreased atherosclerotic plaque development.
- MPO deficiency in mice led to alleviated inflammation, reduced oxidative stress, improved endothelial function, and significantly impacted plaque formation.
- MPO inhibition and deficiency markedly reduced neointima formation after vascular injury, while neutrophil transfer from wild-type mice enhanced it.
Conclusions:
- Myeloperoxidase plays a central role in the pathogenesis of atherosclerosis.
- Pharmacological inhibition of MPO presents a viable therapeutic strategy for preventing and treating atherosclerosis.
- MPO inhibition is also effective in preventing restenosis following vascular injury.
