Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 23, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn051
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Hypochlorite-modified high-density lipoprotein acts as a sink for myeloperoxidase in vitro
1 Medical University of Graz, Center of Molecular Medicine, Institute of Molecular Biology and Biochemistry, A-8010 Graz, Austria
2 BOKU - University of Natural Resources and Applied Life Sciences, Department of Chemistry, Division of Biochemistry, A-1190 Vienna, Austria
** Corresponding author Tel: +43-316-380-4208, Fax: +43-316-380-9615, e-mail: ernst.malle{at}meduni-graz.at
Aims: Myeloperoxidase (MPO), a cardiovascular risk factor in humans, is an in vivo catalyst for lipoprotein modification via intermediate formation of reactive chlorinating species. Among the different lipoprotein classes, antiatherogenic high-density lipoprotein (HDL) represents a major target for modification by hypochlorous acid (HOCl), generated from H2O2 by MPO in the presence of physiological chloride concentrations. As MPO was identified as an HDL-associated protein that could facilitate selective oxidative modification of its physiological carrier, the aim of the present study was to investigate whether and to what extent modification of HDL by HOCl affects the binding affinity of MPO in vitro.
Methods and results: We show that binding affinity of 125I-labelled MPO to HDL markedly increases as a function of increasing extent of HOCl modification of HDL. In contrast to native HDL, HOCl-HDL potently inhibits MPO binding/uptake by endothelial cells and effectively attenuates metabolism of MPO by macrophages. Reduction of HOCl-generated, HDL-associated chloramines with methionine strongly impaired binding affinity of MPO towards HDL. This indicates that N-chloramines are regulators of the high affinity interaction between HOCl-HDL and positively charged MPO. Most importantly, the presence of HOCl-HDL is almost without effect on the halogenating activity of MPO.
Conclusions: We propose that MPO-dependent modification of HDL and concomitant increase in the binding affinity for MPO could generate a vicious cycle of MPO transport to and MPO-dependent modification at sites of chronic inflammation.
KEYWORDS Hypochlorous acid; apoA-I; inflammation; neutrophils; MPO-hydrogen peroxide-halide system
Time for primary review: 24 days
* Present address: Medical University of Graz, Center for Theoretical-Clinical Medicine II, Institute of Experimental and Clinical Pharmacology, A-8010 Graz, Austria
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