Myeloperoxidase: an inflammatory enzyme for generating dysfunctional high density lipoprotein.

PURPOSE OF REVIEW: 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. RECENT
FINDINGS: 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.
SUMMARY: 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.