Nearly 63 million people (20% of the US population) are eligible for VA benefits and services because they are veterans, family members or survivors of veterans. Cardiovascular diseases (CVD) contribute to significant morbidity and mortality of the military veterans and civilians (CDC/National Center for Health Statistics). I have been associated with VA and non-VA funded clinician-scientists and basic researchers for the past 20 years. I am also a VA funded investigator. The overall focus of my research as a VA funded scientist is to investigate the causal role of inflammation, inflammatory cytokines and chemokines, and NF-?B activation in CVD. Since inflammation is a critical component in the pathogenesis of CVD, and CVD are the major contributing factors for morbidity and mortality within both military veteran and civilian populations of both sexes, my studies are highly relevant to the VA mission. Furthermore, hypertension, diabetes, obesity and smoking predispose veterans and civilians alike to CVD, my ongoing studies are timely and critical in further understanding the pathophysiology of these chronic diseases. Using the most promising research strategies and problem-solving approaches, my goal is to identify newer therapeutic targets in CVD. TRAF3 Interacting Protein 2 (TRAF3IP2) is a cytoplasmic adapter molecule and an upstream regulator of at least three major signal transduction pathways that are known to play a pathological role in ischemic cardiac diseases. TRAF3IP2 activates IKK/NF-?B, JNK/AP-1 and p38 MAPK, and induces the expression of multiple cytokines and chemokines with negative myocardial inotropic effects. It also regulates the expression of collagens and MMPs. TRAF3IP2 is a critical intermediate in IL-17 signaling, another proinflammatory cytokine involved in ischemic cardiac disease. Our preliminary results show that TRAF3IP2 also plays a role in IL-18 signaling. In fact, we found that TRAF3IP2 binds the TIR (The Toll/Il-1 Receptor)-domain containing IL-18 receptor via binding motifs that appear to be different from those responsible for TRAF3IP2/IL-17R binding. Bioinformatics revealed that TRAF3IP2 could also associate with IL-1RacP (Interleukin 1 Receptor Accessory Protein), an IL- 1? receptor. We previously reported that TRAF3IP2 also plays a role in LPS/Toll-like receptor 4-mediated cardiomyocyte contractile dysfunction, suggesting that targeting TRAF3IP2 could blunt IL-17, IL-18, IL-1 and LPS signaling, all of which contribute causally to various cardiac pathologies, including cardiac ischemic injury. Utilizing both in vivo (genetic and interventional) and in vitro (cardiomyocytes and cardiac fibroblasts) models, my ongoing studies are examining the relationship between TRAF3IP2, inflammation and heart failure (HF) of ischemic/non-ischemic origin in vivo and the underlying molecular mechanisms in vitro. My long-term goal is to develop therapeutic strategies to inhibit TRAF3IP2 expression. Recently, we targeted TRAF3IP2 by UTMD (ultrasound-targeted microbubble destruction)-mediated delivery of AS-ODN into LV, and demonstrated significant reduction in cardiac TRAF3IP2 expression, myocardial injury (infarct size), adverse remodeling and HF development. In addition, my ongoing studies are focused on unraveling the roles of the RNA binding protein Larp6 (stimulates collagen I and III expression) and the membrane-anchored protein RECK (inhibits multiple MMPs, ADAMs, EGFR, uPA and gp130) in adverse cardiac remodeling and HF development. !!

Public Health Relevance

Cardiovascular diseases (CVD) are the major causes of morbidity and mortality in veterans. For two decades, my research focused on dissecting the molecular mechanisms underlying the initiation and progression of inflammatory CVD, has identified four potential therapeutic targets: IL-18 (Interleukin-18), TRAF3IP2 (TRAF3 Interacting Protein 2), Larp6 (La Ribonucleoprotein Domain Family Member 6), and RECK (Reversion Inducing Cysteine Rich Protein with Kazal Motifs. Increased expression of IL-18 and TRAF3IP2 play a causal role in myocardial injury, adverse cardiac remodeling, and HF development. Larp6, a RNA-bing protein, plays a role in collagen synthesis. RECK inhibits multiple mediators involved in adverse cardiac remodeling. My goal of determining if neutralizing IL-18, inhibiting TRAF3IP2 or Larp6, or inducing RECK can blunt progression of CVD is highly relevant to veterans and the mission of the Veterans Health Care System.

National Institute of Health (NIH)
Veterans Affairs (VA)
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Research Career Scientist (RCSR)
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Harry S. Truman Memorial VA Hospital
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Das, Nitin A; Carpenter, Andrea J; Yoshida, Tadashi et al. (2018) TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. J Mol Cell Cardiol 121:107-123
Alt, Eckhard U; Barabadi, Zahra; Pfnür, Andreas et al. (2018) TRAF3IP2, a novel therapeutic target in glioblastoma multiforme. Oncotarget 9:29772-29788
Aroor, Annayya R; Das, Nitin A; Carpenter, Andrea J et al. (2018) Glycemic control by the SGLT2 inhibitor empagliflozin decreases aortic stiffness, renal resistivity index and kidney injury. Cardiovasc Diabetol 17:108
Padilla, Jaume; Carpenter, Andrea J; Das, Nitin A et al. (2018) TRAF3IP2 mediates high glucose-induced endothelin-1 production as well as endothelin-1-induced inflammation in endothelial cells. Am J Physiol Heart Circ Physiol 314:H52-H64
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