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.
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
Protein quality control and metabolic homeostasis are integral to maintaining cardiac function during stress; however, little is known about if or how these systems interact. Here we demonstrate that C terminus of HSC70-interacting protein (CHIP), a regulator of protein quality control, influences the metabolic response to pressure overload by direct regulation of the catalytic α subunit of AMPK. Induction of cardiac pressure overload in
Jonathan C. Schisler, Carrie E. Rubel, Chunlian Zhang, Pamela Lockyer, Douglas M. Cyr, Cam Patterson
Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3′ untranslated region of
Pankaj Arora, Connie Wu, Abigail May Khan, Donald B. Bloch, Brandi N. Davis-Dusenbery, Anahita Ghorbani, Ester Spagnolli, Andrew Martinez, Allicia Ryan, Laurel T. Tainsh, Samuel Kim, Jian Rong, Tianxiao Huan, Jane E. Freedman, Daniel Levy, Karen K. Miller, Akiko Hata, Federica del Monte, Sara Vandenwijngaert, Melissa Swinnen, Stefan Janssens, Tara M. Holmes, Emmanuel S. Buys, Kenneth D. Bloch, Christopher Newton-Cheh, Thomas J. Wang
The heparan sulfate proteoglycan (HSPG) syndecan-1 (SDC1) acts as a major receptor for triglyceride-rich lipoprotein (TRL) clearance in the liver. We sought to identify the relevant apolipoproteins on TRLs that mediate binding to SDC1 and determine their clinical relevance. Evidence supporting ApoE as a major determinant arose from its enrichment in TRLs from mice defective in hepatic heparan sulfate (
Jon C. Gonzales, Philip L.S.M. Gordts, Erin M. Foley, Jeffrey D. Esko
Heterozygous loss-of-function
Ping Ye, Wenhao Chen, Jie Wu, Xiaofan Huang, Jun Li, Sihua Wang, Zheng Liu, Guohua Wang, Xiao Yang, Peng Zhang, Qiulun Lv, Jiahong Xia
Atrial fibrillation (AF) is a highly prevalent arrhythmia with pronounced morbidity and mortality. Inward-rectifier K+ current (
Xiaobin Luo, Zhenwei Pan, Hongli Shan, Jiening Xiao, Xuelin Sun, Ning Wang, Huixian Lin, Ling Xiao, Ange Maguy, Xiao-Yan Qi, Yue Li, Xu Gao, Deli Dong, Yong Zhang, Yunlong Bai, Jing Ai, Lihua Sun, Hang Lu, Xiao-Yan Luo, Zhiguo Wang, Yanjie Lu, Baofeng Yang, Stanley Nattel
Serine palmitoyltransferase (SPT) is the first and rate-limiting enzyme of the de novo biosynthetic pathway of sphingomyelin (SM). Both SPT and SM have been implicated in the pathogenesis of atherosclerosis, the development of which is driven by macrophages; however, the role of SPT in macrophage-mediated atherogenesis is unknown. To address this issue, we have analyzed macrophage inflammatory responses and reverse cholesterol transport, 2 key mediators of atherogenesis, in SPT subunit 2–haploinsufficient (
Mahua Chakraborty, Caixia Lou, Chongmin Huan, Ming-Shang Kuo, Tae-Sik Park, Guoqing Cao, Xian-Cheng Jiang
Myocardial hypertrophy is an adaptation to increased hemodynamic demands. An increase in heart tissue must be matched by a corresponding expansion of the coronary vasculature to maintain and adequate supply of oxygen and nutrients for the heart. The physiological mechanisms that underlie the coordination of angiogenesis and cardiomyocyte growth are unknown. We report that induction of myocardial angiogenesis promotes cardiomyocyte growth and cardiac hypertrophy through a novel NO-dependent mechanism. We used transgenic, conditional overexpression of placental growth factor (PlGF) in murine cardiac tissues to stimulate myocardial angiogenesis and increase endothelial-derived NO release. NO production, in turn, induced myocardial hypertrophy by promoting proteasomal degradation of regulator of G protein signaling type 4 (RGS4), thus relieving the repression of the Gβγ/PI3Kγ/AKT/mTORC1 pathway that stimulates cardiomyocyte growth. This hypertrophic response was prevented by concomitant transgenic expression of RGS4 in cardiomyocytes. NOS inhibitor L-NAME also significantly attenuated RGS4 degradation, and reduced activation of AKT/mTORC1 signaling and induction of myocardial hypertrophy in PlGF transgenic mice, while conditional cardiac-specific PlGF expression in eNOS knockout mice did not induce myocardial hypertrophy. These findings describe a novel NO/RGS4/Gβγ/PI3Kγ/AKT mechanism that couples cardiac vessel growth with myocyte growth and heart size.
Irina M. Jaba, Zhen W. Zhuang, Na Li, Yifeng Jiang, Kathleen A. Martin, Albert J. Sinusas, Xenophon Papademetris, Michael Simons, William C. Sessa, Lawrence H. Young, Daniela Tirziu
In patients with heart failure, reactivation of a fetal gene program, including atrial natriuretic peptide (
Mathias Hohl, Michael Wagner, Jan-Christian Reil, Sarah-Anne Müller, Marcus Tauchnitz, Angela M. Zimmer, Lorenz H. Lehmann, Gerald Thiel, Michael Böhm, Johannes Backs, Christoph Maack
Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific
Roland Klingenberg, Norbert Gerdes, Robert M. Badeau, Anton Gisterå, Daniela Strodthoff, Daniel F.J. Ketelhuth, Anna M. Lundberg, Mats Rudling, Stefan K. Nilsson, Gunilla Olivecrona, Stefan Zoller, Christine Lohmann, Thomas F. Lüscher, Matti Jauhiainen, Tim Sparwasser, Göran K. Hansson