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.
Ischemic heart disease (IHD) remains a significant cause of morbidity and mortality in the US, and is the most frequent indication for hospitalization within the Veterans Health Care System. Understanding the molecular mechanisms fundamental to IHD will help us identify newer and better targets for therapeutic intervention. The primary goal of this proposal is to understand the expression, regulation and role of TRAF3 interacting protein 2 (TRAF3IP2), an adapter molecule and upstream regulator of IKK/NF-B and JNK/AP-1, which we believe is central to ischemia/reperfusion-induced myocardial injury, dysfunction, and adverse remodeling. Targeting TRAF3IP2 will blunt tissue injury and associated morbidity and mortality.
|Brown, Scott M; Smith, Cassandra E; Meuth, Alex I et al. (2017) Dipeptidyl Peptidase-4 Inhibition With Saxagliptin Ameliorates Angiotensin II-Induced Cardiac Diastolic Dysfunction in Male Mice. Endocrinology 158:3592-3604|
|Erikson, John M; Valente, Anthony J; Mummidi, Srinivas et al. (2017) Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling. J Biol Chem 292:2345-2358|
|Aroor, Annayya R; Habibi, Javad; Kandikattu, Hemanth Kumar et al. (2017) Dipeptidyl peptidase-4 (DPP-4) inhibition with linagliptin reduces western diet-induced myocardial TRAF3IP2 expression, inflammation and fibrosis in female mice. Cardiovasc Diabetol 16:61|
|Sakamuri, Siva Sankara Vara Prasad; Higashi, Yusuke; Sukhanov, Sergiy et al. (2016) TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE(-/-) mice. Atherosclerosis 252:153-60|
|Sakamuri, Siva S V P; Valente, Anthony J; Siddesha, Jalahalli M et al. (2016) TRAF3IP2 mediates aldosterone/salt-induced cardiac hypertrophy and fibrosis. Mol Cell Endocrinol 429:84-92|
|Somanna, Naveen K; Valente, Anthony J; Krenz, Maike et al. (2016) The Nox1/4 Dual Inhibitor GKT137831 or Nox4 Knockdown Inhibits Angiotensin-II-Induced Adult Mouse Cardiac Fibroblast Proliferation and Migration. AT1 Physically Associates With Nox4. J Cell Physiol 231:1130-41|
|Yariswamy, Manjunath; Yoshida, Tadashi; Valente, Anthony J et al. (2016) Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction. J Biol Chem 291:19425-36|
|Valente, Anthony J; Irimpen, Anand M; Siebenlist, Ulrich et al. (2014) OxLDL induces endothelial dysfunction and death via TRAF3IP2: inhibition by HDL3 and AMPK activators. Free Radic Biol Med 70:117-28|
|Yoshida, Tadashi; Friehs, Ingeborg; Mummidi, Srinivas et al. (2014) Pressure overload induces IL-18 and IL-18R expression, but markedly suppresses IL-18BP expression in a rabbit model. IL-18 potentiates TNF-?-induced cardiomyocyte death. J Mol Cell Cardiol 75:141-51|