title: Neutrophil-derived myeloperoxidase promotes atherogenesis and neointima formation in mice.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology, University of Bonn, Bonn, Germany. Electronic address: Vedat.Tiyerili@ukb.uni-bonn.de.
authors.forename: Vedat
authors.initials: V
authors.lastname: Tiyerili
authors.affiliation: Department of Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Bakary
authors.initials: B
authors.lastname: Camara
authors.affiliation: Department of Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Marc U
authors.initials: MU
authors.lastname: Becher
authors.affiliation: Department of Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Schrickel
authors.affiliation: Institute for Clinical Chemistry, University of Bonn, Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Department of Cardiology, Heart Center, University of Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Mollenhauer
authors.affiliation: Department of Cardiology, Heart Center, University of Cologne, Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.affiliation: Department of Cardiology, University of Bonn, Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.affiliation: Department of Cardiology, University of Bonn, Bonn, Germany.
authors.forename: René P
authors.initials: RP
authors.lastname: Andrié
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058426:Neointima / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism*
chemical_list: D009195:Peroxidase
keywords: 4-ABAH; Atherosclerosis; Cardiovascular disease; Myeloperoxidase; Neointimal hyperplasia