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

Abstract

Edited by Dennis R. VoelkerRe-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 IB 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-B 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 destructionmediated 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-B and JNK. Therefore, TRAF3IP2 could be a potential therapeutic target in ischemic heart disease.Ischemic heart disease is a leading cause of morbidity and mortality worldwide (1). Although reperfusion of the ischemic myocardium is the primary goal of reducing myocardial injury and dysfunction, paradoxically it can also produce pathological effects by the (i) excessive generation of reactive oxygen and nitrogen species, (ii) activation of the redox-sensitive dimeric transcription factors NF-B and AP-1, (iii) up-regulation of inflammatory mediators, (iv) recruitment and activation of immune and inflammatory cells, and (v) induction of cardiomyocyte apoptosis, which ultimately results in myocardial injury, dysfunction (ischemia/reperfusion injury or I/R injury), and adverse remodeling (2, 3). Despite progress in our understanding of its underlying molecular mechanisms, myocardial injury post-I/R remains an important clinical problem.A number of studies have firmly established causal roles for the nuclear transcription factors NF-B and AP-1 in myocardial I/R injury (4 -12). Various stimuli, including oxidative stress, cytokines, and growth factors, activate NF-B by inducing the hyperphosphorylation and degradation of its inhibitory subunit IB. A multiprotein complex comprised of IKK␣, IKK␤, and a regulatory subunit IK...

c-Jun N-Terminal Kinases (JNKs) in Myocardial and Cerebral Ischemia/Reperfusion Injury

“…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 JNK. Ischemia/reperfusion up-regulates TRAF3IP2 expression in the heart, and its gene deletion, in a conditional cardiomyocyte-specific manner, significantly attenuates ischemia/reperfusion-induced oxidative stress, IKK/NF-κB and JNK/AP-1 activation, inflammatory cytokine, chemokine, and adhesion molecule expression, immune cell infiltration, myocardial injury, and contractile dysfunction (Erikson et al, 2017 ).…”

Acute sleep deprivation induces cardioprotection against ischemia/ reperfusion injury through reducing inflammatory responses: the role of central GABA-A receptors

“…Blocking GABA-A receptors increased this marker of myocardial injury and administration of bicuculline prior to SD attenuated the protective effects of SD. In this regard, Erikson et al (2017) demonstrated a considerable rise in LDH levels following myocardial IR, however these levels were lower as compared to chronic sleep deprivation (Periasamy et al 2015;Erikson et al 2017). In the current study, the myocardial hemodynamic parameters were studied to reflect cardiac functions.…”

Aldehyde Dehydrogenase-2 Attenuates Myocardial Remodeling and Contractile Dysfunction Induced by a High-Fat Diet

“…We suggest that the protective effect of ALDH2 is due to inhibition of JNK/AP-1 pathway. In the heart, both JNK and AP-1 are key regulators of myocardial remodeling [11,29]. In addition, hypertension-induced cardiac dysfunction is associated with increased AP-1 activity [5].…”