Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex
Ying Huang, … , Ulf Landmesser, Stanley L. Hazen
Ying Huang, … , Ulf Landmesser, Stanley L. Hazen
Published August 1, 2013
Citation Information: J Clin Invest. 2013;123(9):3815-3828. https://doi.org/10.1172/JCI67478.
View: Text | PDF
Research Article Cardiology

Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex

Abstract

Myeloperoxidase (MPO) and paraoxonase 1 (PON1) are high-density lipoprotein–associated (HDL-associated) proteins mechanistically linked to inflammation, oxidant stress, and atherosclerosis. MPO is a source of ROS during inflammation and can oxidize apolipoprotein A1 (APOA1) of HDL, impairing its atheroprotective functions. In contrast, PON1 fosters systemic antioxidant effects and promotes some of the atheroprotective properties attributed to HDL. Here, we demonstrate that MPO, PON1, and HDL bind to one another, forming a ternary complex, wherein PON1 partially inhibits MPO activity, while MPO inactivates PON1. MPO oxidizes PON1 on tyrosine 71 (Tyr71), a modified residue found in human atheroma that is critical for HDL binding and PON1 function. Acute inflammation model studies with transgenic and knockout mice for either PON1 or MPO confirmed that MPO and PON1 reciprocally modulate each other’s function in vivo. Further structure and function studies identified critical contact sites between APOA1 within HDL, PON1, and MPO, and proteomics studies of HDL recovered from acute coronary syndrome (ACS) subjects revealed enhanced chlorotyrosine content, site-specific PON1 methionine oxidation, and reduced PON1 activity. HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, whereupon PON1 binding partially inhibits MPO activity, and MPO promotes site-specific oxidative modification and impairment of PON1 and APOA1 function.

Authors

Ying Huang, Zhiping Wu, Meliana Riwanto, Shengqiang Gao, Bruce S. Levison, Xiaodong Gu, Xiaoming Fu, Matthew A. Wagner, Christian Besler, Gary Gerstenecker, Renliang Zhang, Xin-Min Li, Anthony J. DiDonato, Valentin Gogonea, W.H. Wilson Tang, Jonathan D. Smith, Edward F. Plow, Paul L. Fox, Diana M. Shih, Aldons J. Lusis, Edward A. Fisher, Joseph A. DiDonato, Ulf Landmesser, Stanley L. Hazen

×

Figure 2

MPO and PON1 inhibit each other’s activity in vivo.

Options: View larger image (or click on image) Download as PowerPoint
MPO and PON1 inhibit each other’s activity in vivo. (A) PON1 KO, WT, or ...
(A) PON1 KO, WT, or PON1 Tg animals were injected i.p. with normal saline (Bl) or thioglycollate broth (T). Twenty-four hours later, peritoneal lavages were performed. Where indicated, mice were injected with zymosan (Z) 24 hours after thioglycollate, and peritoneal lavage was performed 4 hours later. Chlorotyrosine (ClTyr) content (normalized to the precursor amino acid tyrosine [Tyr]) in soluble proteins recovered from peritoneal lavage was determined by stable isotope dilution LC/MS/MS analysis. (B) MPO KO, WT, or MPO Tg animals were injected i.p. with normal saline or zymosan (Z). After 72 hours of subacute peritonitis, serum was isolated and paraoxonase activity was measured.