Journal article
Transforming Growth Factor-α Acts in Hypothalamic Paraventricular Nucleus to Upregulate ERK1/2 Signaling and Expression of Sympathoexcitatory Mediators in Heart Failure Rats
Neuroscience, Vol.483, pp.13-23
12/2021
DOI: 10.1016/j.neuroscience.2021.12.030
PMCID: PMC8837700
PMID: 34968668
Abstract
Activation of epidermal growth factor receptor (EGFR) tyrosine kinase is associated with increased extracellular signal-regulated kinase (ERK) 1/2 signaling in the hypothalamic paraventricular nucleus (PVN), which contributes to the sympathetic excitation in heart failure (HF). Transforming growth factor (TGF)-α is a major endogenous ligand for EGFR. The present study sought to determine whether TGF-α increases in the PVN in HF and promotes the activation of EGFR to increase ERK1/2 activity. Male rats received bilateral PVN microinjections of an EGFR siRNA or a scrambled siRNA followed by an intracerebroventricular (ICV) injection of TGF-α or vehicle one week later. In rats pretreated with the scrambled siRNA, ICV TGF-α increased phosphorylated (p-) EGFR and upregulated the expression of p-ERK1/2 and mRNA levels of proinflammatory cytokines (PICs) and renin-angiotensin system (RAS) components in the PVN, when compared with the untreated age-matched control rats. These responses to ICV TGF-α were significantly attenuated in rats pretreated with the EGFR siRNA. Furthermore, bilateral PVN microinjection of a TGF-α siRNA in HF rats significantly decreased the elevated levels of TGF-α, p-EGFR, p-ERK1/2 and the mRNA expression of PICs and RAS components in the PVN, compared with the HF rats treated with a scrambled siRNA. The TGF-α siRNA-treated HF rats also exhibited lower plasma norepinephrine levels and improved peripheral manifestations of HF. These data suggest that TGF-α expression is upregulated in the PVN in HF and induces the activation of EGFR-mediated ERK1/2 signaling to augment the inflammation and RAS activity that drives sympathetic excitation in HF.
Keywords: P44/42 mitogen-activated protein kinase; epidermal growth factor receptor; hypothalamic paraventricular nucleus; inflammatory cytokines; renin-angiotensin system; sympathetic excitation.
Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.
Details
- Title: Subtitle
- Transforming Growth Factor-α Acts in Hypothalamic Paraventricular Nucleus to Upregulate ERK1/2 Signaling and Expression of Sympathoexcitatory Mediators in Heart Failure Rats
- Creators
- Yang YuEthan ChenRobert M WeissRobert B FelderShun-Guang Wei
- Resource Type
- Journal article
- Publication Details
- Neuroscience, Vol.483, pp.13-23
- DOI
- 10.1016/j.neuroscience.2021.12.030
- PMID
- 34968668
- PMCID
- PMC8837700
- NLM abbreviation
- Neuroscience
- ISSN
- 0306-4522
- eISSN
- 1873-7544
- Grant note
- DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute; DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs; DOI: 10.13039/100006379, name: Office of Research and Development; DOI: 10.13039/100007217, name: Health Services Research and Development; DOI: 10.13039/100007496, name: Biomedical Laboratory Research and Development, VA Office of Research and Development; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 HL136149, R01 HL-139521, HL-155091, S10 OD019941
- Language
- English
- Date published
- 12/2021
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984204076302771
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