# Brain ERK1/2 Signaling and Sympathetic Excitation in Heart Failure

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $435,165

## Abstract

Heart failure with impaired systolic function (HF) is a common malady of the aging population, with dire
personal and socioeconomic consequences. The past 2 decades have seen little progress in the
development of new pharmaceutical agents to treat HF. A major factor contributing to the progression of
HF and adverse outcomes is exaggerated sympathetic nervous system activity. Current pharmacological
treatments for HF target the peripheral effects of this augmented sympathetic nerve activity, but not the
central nervous system source. Recent studies in my laboratory have implicated the extracellular signal-
regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway as an
obligatory step leading to sympathetic excitation by many of the neurochemicals (i.e., angiotensin II,
aldosterone, pro-inflammatory cytokines) that are known to be upregulated in key cardiovascular regulatory
regions of the HF brain – effectively acting as a final common pathway for these excitatory agonists.
Working with a rat model of ischemia-induced HF that closely mimics systolic HF in humans, we found that
reducing brain ERK1/2 activity in these regions – and in particular in the hypothalamic paraventricular
nucleus which is a source of presympathetic neurons – reduces sympathetic nerve activity and ameliorates
the peripheral manifestations of HF. In addition, our preliminary studies suggest that this molecular
pathway is amenable to treatment with peripherally administered drug-loaded microparticle preparations.
The present proposal will address both basic mechanistic and potential therapeutic aspects of this
molecular pathway. The mechanistic studies will focus specifically on the role of ERK1/2 signaling in the
hypothalamic paraventricular nucleus, a locus of presympathetic neurons known to contribute to
augmented sympathetic nerve activity in HF. We will examine the role of the epidermal growth factor
receptor as a putative “gateway” to the ERK1/2 signaling pathway by multiple excitatory agonists, the effect
of ERK1/2 signaling on transcription factors that upregulate the expression of excitatory agonists, the effect
of ERK1/2 signaling on a potassium channel mechanisms that may increase the excitability of
presympathetic neurons. The therapeutic studies will explore the possibility that an advanced drug delivery
system that facilitates passage of drug across the blood brain barrier can reduce brain ERK1/2 signaling
and thereby reduce sympathetic nerve activity to improve peripheral manifestations of HF and survival in
HF - a critical translational issue. We anticipate that these studies will lead to better understanding of the
role of brain ERK1/2 signaling in sympathetic excitation and will lay the groundwork for the development of
novel pharmacological approaches to the treatment of HF.

## Key facts

- **NIH application ID:** 9834977
- **Project number:** 5R01HL136149-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Robert B Felder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $435,165
- **Award type:** 5
- **Project period:** 2016-12-23 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9834977

## Citation

> US National Institutes of Health, RePORTER application 9834977, Brain ERK1/2 Signaling and Sympathetic Excitation in Heart Failure (5R01HL136149-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9834977. Licensed CC0.

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