Myeloperoxidase: an oxidative pathway for generating dysfunctional high-density lipoprotein

Area of Science:

• Biochemistry
• Cardiovascular Science
• Molecular Biology

Background:

• Atherosclerosis, a major cardiovascular disease, stems from cholesterol accumulation in macrophages.
• High-density lipoprotein (HDL) normally protects against atherosclerosis by facilitating cholesterol removal from macrophages via the ATP-binding cassette transporter A1 (ABCA1) pathway.
• The mechanisms by which HDL loses its protective function in atherosclerosis are not fully understood.

Purpose of the Study:

• To investigate the role of myeloperoxidase (MPO) in the dysfunction of HDL in patients with cardiovascular disease.
• To determine how MPO-induced oxidation of apolipoprotein A-I (apoA-I) affects HDL's ability to promote cholesterol efflux and its maturation.

Main Methods:

• Mass spectrometry was used to detect MPO-specific oxidation products (3-chlorotyrosine and 3-nitrotyrosine) in HDL from cardiovascular disease patients.
• In vitro experiments assessed the impact of MPO-mediated oxidation of purified apoA-I on ABCA1-dependent cholesterol efflux and lecithin:cholesterol acyltransferase (LCAT) activity.
• Biochemical analyses identified specific amino acid residues modified by MPO oxidation.

Main Results:

• HDL from cardiovascular disease patients showed elevated levels of MPO-derived 3-chlorotyrosine and 3-nitrotyrosine.
• MPO oxidation of apoA-I significantly impaired its ability to promote cholesterol efflux from macrophages via ABCA1.
• Oxidized apoA-I lost its capacity to activate LCAT, a key enzyme in HDL maturation, with tyrosine chlorination and methionine oxidation implicated in these functional losses.

Conclusions:

• Myeloperoxidase (MPO) contributes to HDL dysfunction in cardiovascular disease by oxidizing apolipoprotein A-I (apoA-I).
• MPO-induced apoA-I oxidation impairs critical steps in cholesterol efflux and HDL maturation, suggesting a novel pathway for generating dysfunctional HDL in humans.