# TRAF3IP2 in Adverse Cardiac Remodeling and Heart Failure

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2020 · —

## Abstract

According to the US Department of Veterans Affairs, heart failure (HF) and associated complications
are one of the main reasons for hospital readmissions and death in the Veterans Health Care System. In fact,
above 40 years of age, the lifetime risk of developing HF is one in 5, and readmissions occur within 30 days of
discharge in 20% of patients older than 65 in the Medicare population and the Veterans Health Care System.
Together, these healthcare systems incurred nearly $37.2 billions for HF care in 2009. A substantial number of
patients develop severe LVH secondary to pressure overload (e.g., hypertension, aortic valve stenosis), and
experience episodic severe congestive HF, hospitalization, and increased mortality.
 Pressure overload-induced left ventricular hypertrophy and transition to heart failure involves activation
of both inflammatory and innate immune pathways, with the sustained activation of Nuclear factor kappa B
(NF-κB) and Activator Protein 1 (AP-1) playing a key role in their pathogenesis.
 Our studies, both published and preliminary, clearly indicate that the cytoplasmic adapter molecule
TRAF3IP2 (TRAF3 Interacting Protein 2) plays a causal role in the pathogenesis of pressure overload-induced
myocardial hypertrophy, fibrosis and dysfunction in a pre-clinical mouse model. Our pilot experiments also
demonstrate TRAF3IP2 expression is increased in both hypertrophic and failing human hearts. Based on these
critical findings, our central hypothesis is that TRAF3IP2 plays a pivotal role in pressure overload-induced
adverse cardiac remodeling and heart failure development by inducing the activation of critical signaling
intermediates like IκB kinase (IKK)/NF-κB and c-Jun N-terminal kinase (JNK)/AP-1, increased expression and
secretion of pro-inflammatory and pro-fibrotic mediators, and excessive production and deposition of altered
extracellular matrix, resulting ultimately in adverse cardiac remodeling and contractile dysfunction. While our
long-term goals are to understand the molecular mechanisms involved in the pathophysiology of myocardial
hypertrophy and its transition to heart failure, and to identify novel therapeutic target(s) for intervention and
treatment, our immediate goals are to determine the etiological role of TRAF3IP2 in the pathogenesis of
pressure overload-induced adverse cardiac remodeling and heart failure development, and to develop an
interventional strategy to target its expression in the heart. To test our central hypothesis, three specific aims
are proposed:
 In Specific Aim 1, we will define the causal role of TRAF3IP2 in pressure overload-induced myocardial
hypertrophy, fibrosis and failure using inducible cardiomyocyte-specific TRAF3IP2 knockout and overexpressor
mice.
 In Specific Aim 2, we will delineate the causal role of TRAF3IP2 in pressure overload-induced LVH,
fibrosis and failure using fibroblast-specific TRAF3IP2 knockout mice.
 In Specific Aim 3, we will establish the effectiveness of UTMD (u...

## Key facts

- **NIH application ID:** 9932904
- **Project number:** 5I01BX004220-03
- **Recipient organization:** HARRY S. TRUMAN MEMORIAL VA HOSPITAL
- **Principal Investigator:** Chandrasekar Bysani
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932904

## Citation

> US National Institutes of Health, RePORTER application 9932904, TRAF3IP2 in Adverse Cardiac Remodeling and Heart Failure (5I01BX004220-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932904. Licensed CC0.

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