TRAF3IP2 in Ischemic Heart Disease

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DESCRIPTION (provided by applicant): Ischemic heart disease (IHD) is a leading cause of death for both men and women in the United States, and is one of the most frequent indications for hospitalization within the Veterans Health Care System. The E3 ubiquitin ligase TRAF3IP2 (TRAF3-interacting protein 2; also known as CIKS or Act1) is an adapter molecule that activates both IKK and JNK, and amplifies autoimmune and inflammatory responses by inducing NF-B- and AP-1-responsive cytokine, chemokine, adhesion molecule and MMP expression. Our preliminary data show that ischemia/reperfusion (IR) upregulates TRAF3IP2 expression in the mouse heart. Notably, TRAF3IP2 gene deletion in a cardiomyocyte-specific manner blunts myocardial injury (infarct size) and dysfunction post-IR (genetic approach). Further, an ultrasound-targeted TRAF3IP2 antisense oligodeoxynucleotide markedly attenuates myocardial infarct post-IR in wild type mice, and was superior to targeting its downstream effectors p65 and JNK1 (interventional approach). Based on these preliminary but critical observations, our central hypothesis is that IR-induced oxidative stress and cytokine expression converge on TRAF3IP2, resulting in the activation of IKK/NF-B and JNK/AP-1 pathways that ultimately lead to myocardial IR injury, dysfunction, and adverse remodeling. Our immediate goal is to understand the expression, regulation and role of TRAF3IP2 in IR injury, and develop strategies to target its expression in a clinically relevant time frame. Our long-term objective is to delineate the causal role of TRAF3IP2 in other models of myocardial injury and inflammation. To address our HYPOTHESIS, the following specific aims are proposed: Specific Aim 1: Define the critical role of TRAF3IP2 in IR-induced myocardial injury and dysfunction in vivo using genetic and interventional approaches Specific Aim 2: Demonstrate that TRAF3IP2 is critical in IR-induced adverse remodeling in vivo Specific Aim 3: Discover potential targets for intervention by (i) Investigating the mechanisms of oxidative stress and cytokine induced TRAF3IP2 expression and regulation, and (ii) Identifying the structural motifs responsible for TRAF3IP2 interaction wit the IL-18 receptor and MyD88. Using both genetic and interventional approaches, these novel and innovative studies will establish TRAF3IP2 as a pivotal regulator of myocardial injury, dysfunction, and adverse remodeling post-IR, and identify it as a better therapeutic target than either NF-B or JNK in IR injury.