Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling

• Published in: The Journal of biological chemistry Vol. 292; no. 6; pp. 2345 - 2358
• Main Authors: Erikson, John M., Valente, Anthony J., Mummidi, Srinivas, Kandikattu, Hemanth Kumar, DeMarco, Vincent G., Bender, Shawn B., Fay, William P., Siebenlist, Ulrich, Chandrasekar, Bysani
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.02.2017; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; cytokine; Gene Deletion; inflammation; ischemia; Mice; Mice, Knockout; Molecular Bases of Disease; myocardial infarction; Myocardial Reperfusion Injury - prevention & control; Myocytes, Cardiac - metabolism; Oxidative Stress; Reactive Nitrogen Species - metabolism; transcription factor; Ventricular Remodeling; cytokine; transcription factor; inflammation; oxidative stress; myocardial infarction; ischemia
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.764522

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, Traf3ip2 gene 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.