Hypochlorite-modified high-density lipoprotein acts as a sink for myeloperoxidase in vitro.
OBJECTIVE
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, anti-atherogenic 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.


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 HDL-associated chloramines with methionine strongly impaired binding affinity of MPO towards HOCl-HDL. This indicates that N-chloramines generated by HOCl 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.
Marsche
Gunther
G
Center for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, A-8010 Graz, Austria.
Furtmüller
Paul G
PG
Obinger
Christian
C
Sattler
Wolfgang
W
Malle
Ernst
E
D002478:Cells, Cultured; D002700:Chloramines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism*
D002700:Chloramines; D008075:Lipoproteins, HDL; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D009195:Peroxidase