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Cell-free Biochemical Fluorometric Enzymatic Assay for High-throughput Measurement of Lipid Peroxidation in High Density Lipoprotein
Published on: October 12, 2017
Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for
Gunther Marsche1, Julia T Stadler1, Julia Kargl1
1Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
Abstract:
Atherosclerosis is a disease of increased oxidative stress characterized by protein and lipid modifications in the vessel wall. One important oxidative pathway involves reactive intermediates generated by myeloperoxidase (MPO), an enzyme present mainly in neutrophils and monocytes. Tandem MS analysis identified MPO as a component of lesion derived high-density lipoprotein (HDL), showing that the two interact in the arterial wall. MPO modifies apolipoprotein A1 (apoA-I), paraoxonase 1 and certain HDL-associated phospholipids in human atheroma. HDL isolated from atherosclerotic plaques depicts extensive MPO mediated posttranslational modifications, including oxidation of tryptophan, tyrosine and methionine residues, and carbamylation of lysine residues. In addition, HDL associated plasmalogens are targeted by MPO, generating 2-chlorohexadecanal, a pro-inflammatory and endothelial barrier disrupting lipid that suppresses endothelial nitric oxide formation. Lesion derived HDL is predominantly lipid-depleted and cross-linked and exhibits a nearly 90% reduction in lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity. Here we provide a current update of the pathophysiological consequences of MPO-induced changes in the structure and function of HDL and discuss possible therapeutic implications and options. Preclinical studies with a fully functional apoA-I variant with pronounced resistance to oxidative inactivation by MPO-generated oxidants are currently ongoing. Understanding the relationships between pathophysiological processes that affect the molecular composition and function of HDL and associated diseases is central to the future use of HDL in diagnostics, therapy, and ultimately disease management.
Insights
Myeloperoxidase (MPO) alters high-density lipoprotein (HDL) in atherosclerosis, impairing its function. This MPO-induced damage to HDL contributes to cardiovascular disease progression.
Area of Science:
- Cardiovascular Biology
- Oxidative Stress Research
- Lipid Metabolism
Background:
- Atherosclerosis involves oxidative stress and modifications to proteins and lipids within the vessel wall.
- Myeloperoxidase (MPO) generates reactive intermediates, contributing to oxidative pathways in diseases like atherosclerosis.
- High-density lipoprotein (HDL) plays a crucial role in cholesterol transport and cardiovascular health.
Purpose of the Study:
- To investigate the interaction between MPO and HDL in the arterial wall during atherosclerosis.
- To elucidate the specific MPO-mediated modifications of HDL components and their functional consequences.
- To explore potential therapeutic strategies targeting MPO-induced HDL dysfunction.
Main Methods:
- Tandem mass spectrometry (MS) to identify MPO in lesion-derived HDL.
- Analysis of MPO-mediated posttranslational modifications on HDL-associated proteins (apoA-I, paraoxonase 1) and phospholipids.
- Assessment of MPO-targeted lipid products, such as 2-chlorohexadecanal.
- Measurement of HDL lipid content, cross-linking, lecithin-cholesterol acyltransferase activity, and cholesterol efflux capacity.
Main Results:
- MPO was identified as a component of lesion-derived HDL, interacting within the arterial wall.
- Extensive MPO-mediated modifications were observed in HDL from atherosclerotic plaques, including protein oxidation and carbamylation.
- MPO targeted HDL-associated plasmalogens, generating pro-inflammatory 2-chlorohexadecanal, which inhibits nitric oxide formation.
- Lesion-derived HDL showed significant lipid depletion, cross-linking, and reduced lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity.
Conclusions:
- MPO significantly alters the structure and function of HDL in atherosclerosis.
- These MPO-induced changes in HDL contribute to its pro-inflammatory and atherogenic properties.
- Targeting MPO-mediated HDL modifications presents a potential therapeutic avenue for managing atherosclerosis.
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