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

摘要: Re-establishing blood supply is the primary goal for reducing myocardial injury in subjects with ischemic heart disease. Paradoxically, reperfusion results nitroxidative stress and a marked inflammatory response heart. TRAF3IP2 (TRAF3 Interacting Protein 2; previously known as CIKS or Act1) an oxidative stress-responsive cytoplasmic adapter molecule that upstream regulator of both IκB kinase (IKK) c-Jun N-terminal (JNK), important mediator autoimmune responses. Here we investigated role ischemia/reperfusion (I/R)-induced stress, inflammation, dysfunction, injury, adverse remodeling. Our data show I/R up-regulates expression heart, its gene deletion, conditional cardiomyocyte-specific manner, significantly attenuates I/R-induced IKK/NF-κB JNK/AP-1 activation, cytokine, chemokine, adhesion expression, immune cell infiltration, contractile dysfunction. Furthermore, Traf3ip2 deletion blunts remodeling 12 weeks post-I/R, evidenced by reduced hypertrophy, fibrosis, Supporting genetic approach, interventional approach using ultrasound-targeted microbubble destruction-mediated delivery phosphorothioated antisense oligonucleotides into LV clinically relevant time frame inhibits wild type mice post-I/R. ameliorating damage targeting appears to be more effective inhibiting downstream signaling intermediates NF-κB JNK. Therefore, could potential therapeutic target