# Targeting TACE, a novel approach to the treatment of sympathetic excitation in heart failure.

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $381,250

## Abstract

Heart failure (HF) is a devastating disease. Debilitation, mortality, and concomitant economic burden
associated with HF all point to the need for new therapies to address this problem more effectively. Increased
pro-inflammatory cytokines (PICs) in periphery and the central nervous system, particularly tumor necrosis
factor-α (TNF-α), have been implicated in the pathophysiology of HF. However, anti-TNF clinical trials targeting
peripheral manifestations of HF have failed to exhibit beneficial significance, indicating that the mechanisms of
TNF-α have not been challenged. Our previous study discovered that TNF-α increases in
cardiovascular/autonomic-related regions of the brain in a rat model of HF and contribute significantly to
sympathetic excitation in that setting. More recently, our preliminary data indicated that TACE, a TNF-α
converting enzyme, is upregulated in the paraventricular nucleus (PVN) of hypothalamus and subfornical organ
(SFO) of the brain, and can alter cardiovascular function and sympathetic drive in HF rats. Unlike other
cytokines, TNF-α is initially produced as a transmembrane protein (tmTNF-α). TACE is responsible for the
cleavage of tmTNF-α to release its mature form, the soluble TNF-α (sTNF-α), to mediate inflammatory and
immune responses. Further evidence indicated that sTNF-α binds predominantly to the TNF receptor 1
(TNFR1) to elicit pro-inflammatory and toxic responses and that tmTNF-α binds preferentially to the TNF
receptor 2 (TNFR2) to display an anti-inflammatory and protective role. This project will underline the role of
the brain TACE in TNF-α–induced inflammatory mechanisms driving the neurohumoral activation in HF. Using
a multifaceted approach including electrophysiology, molecular biology, immunocytochemistry, pharmacology,
and biochemistry in sham-operated and HF rats, this project will determine 1) whether TACE regulates the
balance between sTNF-α and tmTNF-α in SFO and PVN in HF, and what cell types are involved; 2) whether
increased TACE activity and/or decreased TNFR2 expression in brain contribute to the neurohumoral
excitation in HF; 3) whether inhibition of TACE or activation of TNFR2 in the brain has a beneficial effect on
cardiac function and survival rate in HF. These studies will characterize a previously unrecognized role of brain
TACE in neurohumoral activation in HF and will identify a novel anti-TNF target for pharmacological
intervention of HF. Completion of this research project will provide important insights into the anti-cytokine
therapeutic strategy in HF and may also have implications in other cardiovascular disorders like hypertension
and metabolic diseases like obesity or diabetes.

## Key facts

- **NIH application ID:** 9838271
- **Project number:** 5R01HL139521-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Shunguang Wei
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2018-01-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838271

## Citation

> US National Institutes of Health, RePORTER application 9838271, Targeting TACE, a novel approach to the treatment of sympathetic excitation in heart failure. (5R01HL139521-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838271. Licensed CC0.

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