# Stellate Ganglia Nrf2 Signaling and Enhanced Cardiac Sympathetic Tone in Chronic Heart Failure

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $741,512

## Abstract

Abstract
Excessive oxidative stress has been shown to be a potent pathophysiological mediator in multiple disease states.
Cardiac and peripheral sympathetic nerve activity is increased in chronic heart failure, in part, due to augmented
neural inflammation and oxidative stress. Importantly, several major antioxidant enzymes and molecules are
decreased in the cytosol and mitochondria of pre-sympathetic neurons in chronic heart failure. A major regulator
of these antioxidant molecules is the transcription factor, Nrf2. Previous studies from our laboratories have shown
a reduction in Nrf2 in heart failure. Genetic knock down of Nrf2 in the rostral ventrolateral medulla of normal mice
results in significant sympatho-excitation and hypertension. On the other hand, overexpression of Nrf2 results in
sympatho-inhibition in mice with chronic heart failure along with a reduction in oxidative stress and an increase
in several antioxidant enzymes. In order to determine if this mechanism plays a role in cardiac arrhythmogenesis
in the post myocardial infarction (MI) chronic heart failure model we propose here to evaluate the role of Nrf2 in
the stellate ganglia, a source of major sympathetic outflow to the heart. Three specific aims are proposed.
Specific Aim 1: We will determine the time-course changes in neural inflammation-Oxidative stress-Nrf2
signaling in the SG post MI. We will evaluate message and protein for the key molecules involved in maintaining
redox homeostasis in the SG, namely the Nrf2/Keap1 system and its target antioxidant enzymes, including
NQO1, HO1, Catalase, SOD and glutathione peroxidase. We will also assess neural inflammation in the SG by
measuring macrophage infiltration and pro-inflammatory cytokines. Correlations will be made between levels of
Nrf2 and cardiac sympathetic tone across a wide range of cardiac function. Specific Aim 2: We will determine
if selective knockdown and overexpression of Nrf2 in the SG alters cardiac sympathetic tone in normal and CHF
animals by altering ganglionic neuronal excitability. Using Nrf2 and Keap1 floxed mice we will evaluate
antioxidant enzyme expression, redox homeostasis, inflammation and arrhythmia incidence. These molecular
alterations induced by Nrf2 will be evident in SG cell action potential generation. Specific Aim 3: We will
determine if pharmaceutic manipulation of Nrf2 signaling in the SG by local SG delivery of micelle conjugated
dynamic hydrogels with encapsulation of two Nrf2 activators (i.e., Curcumin and sulforaphane) reduces
arrhythmogenesis and improves cardiac function in the post-MI rats. We hypothesize that the redox status and
electrophysiological activity of SG neurons in CHF rats will be partially restored following treatment with Nrf2
activators. Furthermore, these effects will be abolished or attenuated in mice with stellate ganglia Nrf2 deficiency.
We believe that this proposed research will lay a solid scientific foundation for developing a new therapies for
the patien...

## Key facts

- **NIH application ID:** 10990834
- **Project number:** 1R01HL172029-01A1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** HANJUN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $741,512
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990834

## Citation

> US National Institutes of Health, RePORTER application 10990834, Stellate Ganglia Nrf2 Signaling and Enhanced Cardiac Sympathetic Tone in Chronic Heart Failure (1R01HL172029-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10990834. Licensed CC0.

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