title: OxLDL induces endothelial dysfunction and death via TRAF3IP2: inhibition by HDL3 and AMPK activators.
abstract: Oxidized low-density lipoprotein (oxLDL) induces endothelial cell death through the activation of NF-κB and AP-1 pathways. TRAF3IP2 is a redox-sensitive cytoplasmic adapter protein and an upstream regulator of IKK/NF-κB and JNK/AP-1. Here we show that oxLDL-induced death in human primary coronary artery endothelial cells (ECs) was markedly attenuated by the knockdown of TRAF3IP2 or the lectin-like oxLDL receptor 1 (LOX-1). Further, oxLDL induced Nox2/superoxide-dependent TRAF3IP2 expression, IKK/p65 and JNK/c-Jun activation, and LOX-1 upregulation, suggesting a reinforcing mechanism. Similarly, the lysolipids present in oxLDL (16:0-LPC and 18:0-LPC) and minimally modified LDL also upregulated TRAF3IP2 expression. Notably, whereas native HDL3 reversed oxLDL-induced TRAF3IP2 expression and cell death, 15-lipoxygenase-modified HDL3 potentiated its proapoptotic effects. The activators of the AMPK/Akt pathway, adiponectin, AICAR, and metformin, attenuated superoxide generation, TRAF3IP2 expression, and oxLDL/TRAF3IP2-mediated EC death. Further, both HDL3 and adiponectin reversed oxLDL/TRAF3IP2-dependent monocyte adhesion to endothelial cells in vitro. Importantly, TRAF3IP2 gene deletion and the AMPK activators reversed oxLDL-induced impaired vasorelaxation ex vivo. These results indicate that oxLDL-induced endothelial cell death and dysfunction are mediated via TRAF3IP2 and that native HDL3 and the AMPK activators inhibit this response. Targeting TRAF3IP2 could potentially inhibit progression of atherosclerotic vascular diseases.
authors.affiliation: Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.affiliation: Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA; Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Anand M
authors.initials: AM
authors.lastname: Irimpen
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.affiliation: Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA; Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA. Electronic address: bchandra@tulane.edu.
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D016923:Cell Death / Q000187:drug effects; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053440:Lipoproteins, HDL3 / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides; D018808:Transcription Factor AP-1 / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053440:Lipoproteins, HDL3; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C414202:TRAF3IP2 protein, human; D018808:Transcription Factor AP-1; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C099252:oxidized low density lipoprotein; D013481:Superoxides; D055372:AMP-Activated Protein Kinases
keywords: Atherosclerosis; Endothelial dysfunction; Free radicals; NADPH oxidases; Oxidative stress