Myeloperoxidase: an inflammatory enzyme for generating dysfunctional high density lipoprotein.
OBJECTIVE
Evidence indicates that high density lipoprotein (HDL) is cardioprotective and that several mechanisms are involved. One important pathway is a membrane-associated ATP-binding cassette transporter, ABCA1, that clears cholesterol from macrophage foam cells. Anti-inflammatory and antioxidant properties also might contribute to HDL's ability to inhibit atherosclerosis.


RESULTS
Myeloperoxidase targets HDL for oxidation, raising the possibility that the enzyme provides a specific mechanism for generating dysfunctional HDL in humans. Myeloperoxidase-dependent oxidation of apolipoprotein A-I, the major protein in HDL, blocks HDL's ability to remove excess cholesterol from cells by the ABCA1 pathway. Analysis of mutated forms of apoA-I and oxidized apoA-I treated with methionine sulfoxide reductase implicate oxidation of specific tyrosine and methionine residues in impairing the ABCA1 transport activity of apoA-I. The crystal structure of lipid-free apoA-I suggests that such oxidative damage might disrupt negatively charged regions on the protein's surface or alter its remodeling, resulting in conformations that fail to interact with ABCA1.


CONCLUSIONS
Oxidation of HDL by myeloperoxidase may represent a specific molecular mechanism for converting the cardioprotective lipoprotein into a dysfunctional form, raising the possibility that the enzyme represents a potential therapeutic target for preventing vascular disease in humans. Moreover, oxidized HDL might prove useful as a blood marker for clinically significant cardiovascular disease in humans.
Shao
Baohai
B
Department of Medicine, University of Washington, Seattle, 98195, USA.
Oda
Michael N
MN
Oram
John F
JF
Heinecke
Jay W
JW
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000893:Anti-Inflammatory Agents / Q000378:metabolism* / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000494:pharmacology; D051150:Methionine Sulfoxide Reductases; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism*
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D010088:Oxidoreductases; D009195:Peroxidase; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase