# Neural Inflammation and Exercise Pressor Reflex in Heart Failure

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $615,663

## Abstract

Chronic heart failure (CHF) is one of the leading causes of death in the U.S. A primary characteristic of this
disease is elevated sympatho-excitation and exercise intolerance during physical activity. During exercise in
heart failure patients, extreme activation of the sympathetic nervous system is often seen and evokes an
exaggerated pressor response accompanied by hyperventilation. These abnormalities potentially increase
cardiovascular risk during physical activity in these patients. Experimental evidence suggests that 1) the
exaggerated sympatho-excitation during exercise is directly related to an increased sensitivity of the exercise
pressor reflex (EPR); 2) the enhanced mechanically sensitive afferent component of this reflex (i.e.
mechanoreflex) primarily contributes to the exaggerated EPR in CHF and 3) muscle metaboreflex activated by
femoral intra-arterial injection of capsaicin is blunted in CHF rats, which is associated with downregulated
Transient Receptor Potential Vanilloid Type 1 (TRPV1) protein expression in lumbar dorsal root ganglia
(DRGs). The molecular and cellular mechanisms underlying altered mechano- and metabo-sensitive afferent
limb in CHF have not been fully understood. Our preliminary data showed that myocardial infarct (MI) triggered
time-dependent macrophage infiltration into lumbar DRGs, suggesting that a neural inflammatory cascade
occurs in muscle afferent ganglia post MI. We hypothesize that macrophage activation in lumbar DRGs plays a
critical role in muscle afferent sensitization as well as the exaggerated EPR via regulating Kv channels and
glutamatergic signaling in CHF. We also hypothesize that macrophage activation in lumbar DRGs also serves
as an upstream mechanism to cause the TRPV1 channel dysfunction in muscle metabo-sensitive neurons in
CHF. In Aim 1, we propose to determine the time-dependent macrophage infiltration/activation in lumbar
(L4-L6) DRGs in post-MI male and female rats as well as post-MI CX3CR1CreER-tdTomato reporter mice. We will
also plan to identify the pro-inflammatory (M1)/anti-inflammatory (M2) phenotypes of macrophages in lumbar
DRGs post MI. Finally we will determine if pharmacological macrophage inhibition in lumbar DRGs can restore
the exaggerated EPR as well as muscle afferent sensitization in CHF male and female rats. Aim 2 is designed
to address how macrophages influence muscle afferent neuronal excitability post MI. We will determine if local
pharmacological macrophage inhibition in lumbar DRGs can restore altered Kv channels, TRPV1 channel and
glutamatergic dysfunction in CHF male and female rats. We will use highly integrative techniques including
molecular (real-time PCR, western blot, immunofluorescence and tissue clearance), cellular (patch clamp) and
whole animal experiments (measuring EPR function, single afferent recording) to test our hypotheses in this
project. We believe that this proposed research will address important functional and mechanistic issues that
direct...

## Key facts

- **NIH application ID:** 10908449
- **Project number:** 5R01HL169205-02
- **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:** $615,663
- **Award type:** 5
- **Project period:** 2023-08-16 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908449

## Citation

> US National Institutes of Health, RePORTER application 10908449, Neural Inflammation and Exercise Pressor Reflex in Heart Failure (5R01HL169205-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10908449. Licensed CC0.

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