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Silencing Epidermal Growth Factor Receptor in Hypothalamic Paraventricular Nucleus Reduces Extracellular Signal-regulated Kinase 1 and 2 Signaling and Sympathetic Excitation in Heart Failure Rats
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Silencing Epidermal Growth Factor Receptor in Hypothalamic Paraventricular Nucleus Reduces Extracellular Signal-regulated Kinase 1 and 2 Signaling and Sympathetic Excitation in Heart Failure Rats

Yang Yu, Shun-Guang Wei, Robert M Weiss and Robert B Felder
Neuroscience, Vol.463, pp.227-237
02/02/2021
DOI: 10.1016/j.neuroscience.2021.01.025
PMID: 33540053
url
https://www.ncbi.nlm.nih.gov/pmc/articles/8106624View
Open Access

Abstract

•The hypothalamic paraventricular nucleus (PVN) is a source of augmented sympathetic nerve activity in heart failure (HF).•Epidermal growth factor receptor (EGFR) activates extracellular signal-related kinase 1 and 2 (ERK1/2) in PVN of HF rats.•ERK1/2 upregulates PVN expression of excitatory mediators that drive sympathetic activity in HF rats.•siRNA knockdown of EGFR in the PVN reduces sympathetic activity and improves the peripheral manifestations of HF.•Brain EGFR is a potential target for therapeutic intervention in the augmented sympathetic activity that promotes HF progression. Activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling in cardiovascular regulatory regions of the brain contributes to sympathetic excitation in myocardial infarction (MI)-induced heart failure (HF) by increasing brain renin-angiotensin system (RAS) activity, neuroinflammation, and endoplasmic reticulum (ER) stress. The mechanisms eliciting brain ERK1/2 signaling in HF are still poorly understood. We tested the involvement of the epidermal growth factor receptor (EGFR) which, upon activation, stimulates ERK1/2 activity. Adult male Sprague-Dawley rats received bilateral microinjections of a lentiviral vector encoding a small interfering RNA (siRNA) for EGFR, or a scrambled siRNA, into the hypothalamic paraventricular nucleus (PVN), a recognized source of sympathetic overactivity in HF. One week later, coronary artery ligation was performed to induce HF. Four weeks later, the EGFR siRNA-treated HF rats, compared with the scrambled siRNA-treated HF rats, had lower mRNA and protein levels of EGFR, lower levels of phosphorylated (p-) EGFR and p-ERK1/2 and lower mRNA levels of the inflammatory mediators TNF-α, IL-1β and cyclooxygenase-2, the RAS components angiotensin-converting enzyme and angiotensin II type 1a receptor and the ER stress markers BIP and ATF4 in the PVN. They also had lower plasma and urinary norepinephrine levels and improved peripheral manifestations of HF. Additional studies revealed that p-EGFR was increased in the PVN of HF rats, compared with sham-operated control rats. These results suggest that activation of EGFR in the PVN triggers ERK1/2 signaling, along with ER stress, neuroinflammation and RAS activity, in MI-induced HF. Brain EGFR may be a novel target for therapeutic intervention in MI-induced HF.
 Brain p44/42 mitogen-activated protein kinase neuroinflammation renin-angiotensin system endoplasmic reticulum stress

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