Mutual Inhibition
Elevated levels of high density lipoprotein (HDL) are associated with cardiovascular health. HDL functions in cholesterol efflux and transport and has been shown to have anti-inflammatory and antioxidant activities. There are many different HDL-associated proteins and there is increasing evidence that the composition of HDL-associated proteins differs between individuals and may play a role in development of cardiac disease. Ying Huang and colleagues at the Cleveland Clinic examine the interaction of HDL and two HDL-associated proteins, myeloperoxidase (MPO) and paraoxonase 1 (PON1). During inflammation, MPO can oxidize the major protein component of HDL, apolipoprotein A1 (APOA1), and promote atherosclerosis. PON1 has emerged as a mediator of anti-inflammatory, antioxidant and atheroprotective activities of HDL. This study identifies the presence of a functional HDL-MPO-PON1 ternary complex in vivo. During inflammation, PON1 partially inhibits MPO activity and MPO promotes site-specific oxidative modification and impairment of PON1 and APOA1 function. The above image is a cartoon of spherical HDL (green) coupled with PON1 (purple) and MPO (aqua). PON1 interactions with APOA1 are shown in blue and salmon, with the adjacent MPO1 binding site in light blue. Openings to the heme (orange) binding pockets of MPO are in close proximity to APOA1 modifications (black) that are common in atherosclerotic plaques.
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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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