title: Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling.
abstract: Re-establishing blood supply is the primary goal for reducing myocardial injury in subjects with ischemic heart disease. Paradoxically, reperfusion results in nitroxidative stress and a marked inflammatory response in the heart. TRAF3IP2 (TRAF3 Interacting Protein 2; previously known as CIKS or Act1) is an oxidative stress-responsive cytoplasmic adapter molecule that is an upstream regulator of both IκB kinase (IKK) and c-Jun N-terminal kinase (JNK), and an important mediator of autoimmune and inflammatory responses. Here we investigated the role of TRAF3IP2 in ischemia/reperfusion (I/R)-induced nitroxidative stress, inflammation, myocardial dysfunction, injury, and adverse remodeling. Our data show that I/R up-regulates TRAF3IP2 expression in the heart, and its gene deletion, in a conditional cardiomyocyte-specific manner, significantly attenuates I/R-induced nitroxidative stress, IKK/NF-κB and JNK/AP-1 activation, inflammatory cytokine, chemokine, and adhesion molecule expression, immune cell infiltration, myocardial injury, and contractile dysfunction. Furthermore,Traf3ip2gene deletion blunts adverse remodeling 12 weeks post-I/R, as evidenced by reduced hypertrophy, fibrosis, and contractile dysfunction. Supporting the genetic approach, an interventional approach using ultrasound-targeted microbubble destruction-mediated delivery of phosphorothioated TRAF3IP2 antisense oligonucleotides into the LV in a clinically relevant time frame significantly inhibits TRAF3IP2 expression and myocardial injury in wild type mice post-I/R. Furthermore, ameliorating myocardial damage by targeting TRAF3IP2 appears to be more effective to inhibiting its downstream signaling intermediates NF-κB and JNK. Therefore, TRAF3IP2 could be a potential therapeutic target in ischemic heart disease.
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229.
authors.forename: John M
authors.initials: JM
authors.lastname: Erikson
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Mummidi
authors.affiliation: the Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri 65211.|the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri 65201.
authors.forename: Hemanth Kumar
authors.initials: HK
authors.lastname: Kandikattu
authors.affiliation: the Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri 65211.|the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri 65201.|the Departments of Medical Pharmacology and Physiology and.
authors.forename: Vincent G
authors.initials: VG
authors.lastname: DeMarco
authors.affiliation: the Departments of Medical Pharmacology and Physiology and.|the Dalton Cardiovascular Research Center, Columbia, Missouri 65201, and.|Biomedical Sciences, University of Missouri School of Medicine, Columbia, Missouri 65211.
authors.forename: Shawn B
authors.initials: SB
authors.lastname: Bender
authors.affiliation: the Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri 65211.|the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri 65201.|the Departments of Medical Pharmacology and Physiology and.
authors.forename: William P
authors.initials: WP
authors.lastname: Fay
authors.affiliation: Biomedical Sciences, University of Missouri School of Medicine, Columbia, Missouri 65211.|the Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.affiliation: the Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri 65211, chandrasekarb@health.missouri.edu.|the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri 65201.|the Departments of Medical Pharmacology and Physiology and.|the Dalton Cardiovascular Research Center, Columbia, Missouri 65201, and.
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D026361:Reactive Nitrogen Species; C515963:Traf3ip2 protein, mouse
keywords: cytokine; inflammation; ischemia; myocardial infarction; oxidative stress; transcription factor