Journal article
Angiotensin II Type 1a Receptors in the Subfornical Organ Modulate Neuroinflammation in the Hypothalamic Paraventricular Nucleus in Heart Failure Rats
Neuroscience, Vol.381, pp.46-58
06/15/2018
DOI: 10.1016/j.neuroscience.2018.04.012
PMCID: PMC5960439
PMID: 29684507
Abstract
•Central inflammation contributes to neurohumoral excitation in rats with ischemia-induced heart failure (HF).•Angiotensin II induces inflammation in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN).•Preventing upregulation of angiotensin II type 1a receptor (AT1aR) in the SFO in HF reduces inflammation in SFO and PVN.•Preventing upregulation of AT1aR in the SFO in HF also reduces sympathetic excitation and vasopressin release.•Increased circulating angiotensin II likely contributes to neuroinflammation that drives neurohumoral excitation in HF.
Inflammation in the hypothalamic paraventricular nucleus (PVN) contributes to neurohumoral excitation and its adverse consequences in systolic heart failure (HF). The stimuli that trigger inflammation in the PVN in HF are not well understood. Angiotensin II (AngII) has pro-inflammatory effects, and circulating levels of AngII increase in HF. The subfornical organ (SFO), a circumventricular structure that lacks an effective blood–brain barrier and senses circulating AngII, contains PVN-projecting neurons. We hypothesized that activation of AngII type 1a receptors (AT1aR) in the SFO induces neuroinflammation downstream in the PVN. Male rats received SFO microinjections of an adeno-associated virus carrying shRNA for AT1aR, a scrambled shRNA, or vehicle. One week later, some rats were euthanized to confirm the transfection potential and knockdown efficiency of the shRNA. Others underwent coronary artery ligation to induce HF or a sham coronary artery ligation (Sham). Four weeks later, HF rats that received the scrambled shRNA had increased mRNA in SFO and PVN for AT1aR, inflammatory mediators and indicators of neuronal and glial activation, increased plasma levels of AngII, tumor necrosis factor-α, norepinephrine and arginine vasopressin, and impaired cardiac function, compared with Sham rats that received scrambled shRNA. The central abnormalities were ameliorated in HF rats that received AT1aR shRNA, as were plasma norepinephrine and vasopressin. Sham rats that received AT1aR shRNA had reduced SFO AT1aR mRNA but no other changes compared with Sham rats that received scrambled shRNA. The results suggest that activation of AT1aR in the SFO upregulates the neuroinflammation in the PVN that contributes to neurohumoral excitation in HF.
Details
- Title: Subtitle
- Angiotensin II Type 1a Receptors in the Subfornical Organ Modulate Neuroinflammation in the Hypothalamic Paraventricular Nucleus in Heart Failure Rats
- Creators
- Yang Yu - Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, USAShun-Guang Wei - Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, USARobert M Weiss - Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, USARobert B Felder - Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Neuroscience, Vol.381, pp.46-58
- DOI
- 10.1016/j.neuroscience.2018.04.012
- PMID
- 29684507
- PMCID
- PMC5960439
- NLM abbreviation
- Neuroscience
- ISSN
- 0306-4522
- eISSN
- 1873-7544
- Publisher
- Elsevier Ltd
- Grant note
- DOI: 10.13039/100000738, name: Department of Veterans Affairs; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01HL073986, S10 OD019941
- Language
- English
- Date published
- 06/15/2018
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984065388002771
Metrics
29 Record Views