Logo image
Back
TNF-α receptor 1 knockdown in the subfornical organ ameliorates sympathetic excitation and cardiac hemodynamics in heart failure rats
Journal article   Open access   Peer reviewed

TNF-α receptor 1 knockdown in the subfornical organ ameliorates sympathetic excitation and cardiac hemodynamics in heart failure rats

Yang Yu, Shun-Guang Wei, Robert M Weiss and Robert B Felder
American journal of physiology. Heart and circulatory physiology, Vol.313(4), pp.H744-756
10/01/2017
DOI: 10.1152/ajpheart.00280.2017
PMCID: PMC5668605
PMID: 28710070
url
https://doi.org/10.1152/ajpheart.00280.2017View
Published (Version of record) Open Access

Abstract

In systolic heart failure (HF), circulating proinflammatory cytokines upregulate inflammation and renin-angiotensin system (RAS) activity in cardiovascular regions of the brain, contributing to sympathetic excitation and cardiac dysfunction. Important among these is the subfornical organ (SFO), a forebrain circumventricular organ that lacks an effective blood-brain barrier and senses circulating humors. We hypothesized that the tumor necrosis factor-α (TNF-α) receptor 1 (TNFR1) in the SFO contributes to sympathetic excitation and cardiac dysfunction in HF rats. Rats received SFO microinjections of a TNFR1 shRNA or a scrambled shRNA lentiviral vector carrying green fluorescent protein, or vehicle. One week later, some rats were euthanized to confirm the accuracy of the SFO microinjections and the transfection potential of the lentiviral vector. Other rats underwent coronary artery ligation (CL) to induce HF or a sham operation. Four weeks after CL, vehicle- and scrambled shRNA-treated HF rats had significant increases in TNFR1 mRNA and protein, NF-κB activity, and mRNA for inflammatory mediators, RAS components and c-Fos protein in the SFO and downstream in the hypothalamic paraventricular nucleus, along with increased plasma norepinephrine levels and impaired cardiac function, compared with vehicle-treated sham-operated rats. In HF rats treated with TNFR1 shRNA, TNFR1 was reduced in the SFO but not paraventricular nucleus, and the central and peripheral manifestations of HF were ameliorated. In sham-operated rats treated with TNFR1 shRNA, TNFR1 expression was also reduced in the SFO but there were no other effects. These results suggest a key role for TNFR1 in the SFO in the pathophysiology of systolic HF. Activation of TNF-α receptor 1 in the subfornical organ (SFO) contributes to sympathetic excitation in heart failure rats by increasing inflammation and renin-angiotensin system activity in the SFO and downstream in the hypothalamic paraventricular nucleus. Cytokine receptors in the SFO may be a target for central intervention in cardiovascular conditions characterized by peripheral inflammation.
 RNA, Small Interfering - genetics Heart Failure - physiopathology Proto-Oncogene Proteins c-fos - biosynthesis Rats Heart Failure - genetics Male NF-kappa B - metabolism Sympathetic Nervous System - physiopathology Receptors, Tumor Necrosis Factor, Type I - genetics Rats, Sprague-Dawley Coronary Circulation - genetics Gene Knockdown Techniques Tumor Necrosis Factor-alpha - pharmacology Norepinephrine - blood Animals Renin-Angiotensin System Receptors, Tumor Necrosis Factor, Type I - biosynthesis Subfornical Organ - physiopathology Electrocardiography Hemodynamics - drug effects

Details

Metrics

19 Record Views
37 Times Cited - Web of Science
Logo image