title: Advanced oxidation protein products induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling.
abstract: Advanced oxidation protein products (AOPPs) are formed during chronic oxidative stress as a result of reactions between plasma proteins and chlorinated oxidants. Their levels are elevated during various cardiovascular diseases. Because elevated AOPPs serve as independent risk factors for ischemic heart disease, and cardiomyocyte death is a hallmark of ischemic heart disease, we hypothesized that AOPPs will induce cardiomyocyte death. AOPP-modified mouse serum albumin (AOPP-MSA) induced significant death of neonatal mouse cardiomyocytes that was attenuated by knockdown of the receptor for advanced glycation end products, but not CD36. Notably, TRAF3-interacting protein 2 (TRAF3IP2; also known as CIKS or Act1) knockdown blunted AOPP-induced apoptosis. AOPP-MSA stimulated Nox2/Rac1-dependent superoxide generation, TRAF3IP2 expression, and TRAF3IP2-dependent JNK activation. The superoxide anion generating xanthine/xanthine oxidase system and hydrogen peroxide both induced TRAF3IP2 expression. Further, AOPP-MSA induced mitochondrial Bax translocation and release of cytochrome c into cytoplasm. Moreover, AOPP-MSA suppressed antiapoptotic Bcl-2 and Bcl-xL expression. These effects were reversed by TRAF3IP2 knockdown or forced expression of mutant JNK. Similar to its effects in neonatal cardiomyocytes, AOPP-MSA induced adult cardiomyocyte death in part via TRAF3IP2. These results demonstrate for the first time that AOPPs induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK activation in vitro and suggest that AOPPs may contribute to myocardial injury in vivo. Thus TRAF3IP2 may represent a potential therapeutic target in ischemic heart disease.
authors: Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
authors: Anthony J
authors: AJ
authors: Valente
authors: Tadashi
authors: T
authors: Yoshida
authors: Robert A
authors: RA
authors: Clark
authors: Patrice
authors: P
authors: Delafontaine
authors: Ulrich
authors: U
authors: Siebenlist
authors: Bysani
authors: B
authors: Chandrasekar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D062107:Advanced Oxidation Protein Products / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D054879:Halogenation; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D016877:Oxidants / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism / Q000633:toxicity; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D062107:Advanced Oxidation Protein Products; D001798:Blood Proteins; D008562:Membrane Glycoproteins; D009479:Neuropeptides; D016877:Oxidants; C484602:Rac1 protein, mouse; C515963:Traf3ip2 protein, mouse; D013481:Superoxides; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D048670:MAP Kinase Kinase 4; D020830:rac1 GTP-Binding Protein