Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle.
High density lipoprotein (HDL) is the major atheroprotective particle in plasma. Recent studies demonstrate that myeloperoxidase (MPO) binds to HDL in vivo, selectively targeting apolipoprotein A1 (apoA1) of HDL for oxidative modification and concurrent loss in cholesterol efflux and lecithin cholesterol acyl transferase activating activities, generating a "dysfunctional HDL" particle. We now show that (patho)physiologically relevant levels of MPO-catalyzed oxidation result in loss of non-cholesterol efflux activities of HDL including anti-apoptotic and anti-inflammatory functions. One mechanism responsible is shown to involve the loss of modified HDL binding to the HDL receptor, scavenger receptor B1, and concurrent acquisition of saturable and specific binding to a novel unknown receptor independent of scavenger receptors CD36 and SR-A1. HDL modification by MPO is further shown to confer pro-inflammatory gain of function activities as monitored by NF-kappaB activation and surface vascular cell adhesion molecule levels on aortic endothelial cells exposed to MPO-oxidized HDL. The loss of non-cholesterol efflux activities and the gain of pro-inflammatory functions requires modification of the entire particle and can be recapitulated by oxidation of reconstituted HDL particles comprised of apoA1 and nonoxidizable phosphatidylcholine species. Multiple site-directed mutagenesis studies of apoA1 suggest that the pro-inflammatory activity of MPO-modified HDL does not involve methionine, tyrosine, or tryptophan, oxidant-sensitive residues previously mapped as sites of apoA1 oxidation within human atheroma. Thus, MPO-catalyzed oxidation of HDL results not only in the loss of classic atheroprotective reverse cholesterol transport activities of the lipoprotein but also both the loss of non-cholesterol efflux related activities and the gain of pro-inflammatory functions.
Undurti
Arundhati
A
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Huang
Ying
Y
Lupica
Joseph A
JA
Smith
Jonathan D
JD
DiDonato
Joseph A
JA
Hazen
Stanley L
SL
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D018110:Receptors, Lipoprotein / Q000378:metabolism
D016632:Apolipoprotein A-I; D018836:Inflammation Mediators; D008075:Lipoproteins, HDL; D018110:Receptors, Lipoprotein; C031616:high density lipoprotein receptors; D009195:Peroxidase