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

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Figure 6

Methionine oxidation plays a role in PON1 activity and stability.

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Methionine oxidation plays a role in PON1 activity and stability. (A) In...
(A) Inverse correlation between systemic PON1 activity and protein content of ClTyr-isolated HDL from ACS (black ovals; n = 26) and healthy nondiabetic control subjects (white ovals; n = 26) from case-control cohort 1 (see Supplemental Table 1). P value shown is for the Spearman’s rank correlation between PON1 activity level and HDL ClTyr content among both control and ACS subjects. (B) Quantification of site-specific methionine oxidation (methionine sulfoxide) within PON1 recovered from isolated HDL from ACS (n = 10) and healthy nondiabetic control subjects (n = 10) enrolled in case-control cohort 2 (Supplemental Table 2). Results shown are expressed as the peak ratio of peptide harboring the indicated methionine sulfoxide residue or parent (methionine-harboring) peptide relative to the reference peptide, as described in Methods. (C) Isolated human HDL from a healthy donor was incubated with the MPO/H2O2/Cl– system (oxHDL), and then the effect of exposure to either methionine sulfoxide reductase (+MSR) or vehicle control (–MSR) on PON1 activity was determined as described in Methods. PON1 activity is expressed relative to paraoxonase activity measured in HDL prior to exposure to the MPO/H2O2/Cl– system. Data are the mean ± SD of triplicate determinations.