Journal article
Inhibition of Brain Mitogen-Activated Protein Kinase Signaling Reduces Central Endoplasmic Reticulum Stress and Inflammation and Sympathetic Nerve Activity in Heart Failure Rats
Hypertension (Dallas, Tex. 1979), Vol.67(1), pp.229-236
01/2016
DOI: 10.1161/HYPERTENSIONAHA.115.06329
PMCID: PMC4679490
PMID: 26573710
Abstract
Mitogen-activated protein kinase (MAPK) signaling and endoplasmic reticulum (ER) stress in the brain have been implicated in the pathophysiology of hypertension. This study determined whether ER stress occurs in subfornical organ and hypothalamic paraventricular nucleus in heart failure (HF) and how MAPK signaling interacts with ER stress and other inflammatory mediators. HF rats had significantly higher levels of the ER stress biomarkers (glucose-regulated protein 78, activating transcription factor 6, activating transcription factor 4, X-box binding protein 1, P58(IPK), and C/EBP homologous protein) in subfornical organ and paraventricular nucleus, which were attenuated by a 4-week intracerebroventricular infusion of inhibitors selective for p44/42 MAPK (PD98059), p38 MAPK (SB203580), or c-Jun N-terminal kinase (SP600125). HF rats also had higher mRNA levels of tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, and nuclear factor-κB p65, and a lower mRNA level of IκB-α, in subfornical organ and paraventricular nucleus, compared with SHAM rats, and these indicators of increased inflammation were attenuated in the HF rats treated with the MAPK inhibitors. Plasma norepinephrine level was higher in HF rats than in SHAM rats but was reduced in the HF rats treated with PD98059 and SB203580. A 4-week intracerebroventricular infusion of PD98059 also improved some hemodynamic and anatomic indicators of left ventricular function in HF rats. These data demonstrate that ER stress increases in the subfornical organ and paraventricular nucleus of rats with ischemia-induced HF and that inhibition of brain MAPK signaling reduces brain ER stress and inflammation and decreases sympathetic excitation in HF. An interaction between MAPK signaling and ER stress in cardiovascular regions of the brain may contribute to the development of HF.
Details
- Title: Subtitle
- Inhibition of Brain Mitogen-Activated Protein Kinase Signaling Reduces Central Endoplasmic Reticulum Stress and Inflammation and Sympathetic Nerve Activity in Heart Failure Rats
- Creators
- Shun-Guang Wei - From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (S.-G.W., Y.Y., R.M.W., R.B.F.); and Research Service, Veterans Affairs Medical Center, Iowa City, IA (R.B.F.)Yang Yu - From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (S.-G.W., Y.Y., R.M.W., R.B.F.); and Research Service, Veterans Affairs Medical Center, Iowa City, IA (R.B.F.)Robert M Weiss - From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (S.-G.W., Y.Y., R.M.W., R.B.F.); and Research Service, Veterans Affairs Medical Center, Iowa City, IA (R.B.F.)Robert B Felder - From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (S.-G.W., Y.Y., R.M.W., R.B.F.); and Research Service, Veterans Affairs Medical Center, Iowa City, IA (R.B.F.). robert-felder@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.67(1), pp.229-236
- DOI
- 10.1161/HYPERTENSIONAHA.115.06329
- PMID
- 26573710
- PMCID
- PMC4679490
- NLM abbreviation
- Hypertension
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Publisher
- United States
- Grant note
- R01 HL096671 / NHLBI NIH HHS S10 OD019941 / NIH HHS S10OD019941 / NIH HHS R01HL073986 / NHLBI NIH HHS R01 HL073986 / NHLBI NIH HHS R01HL096671 / NHLBI NIH HHS
- Language
- English
- Date published
- 01/2016
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984065490602771
Metrics
33 Record Views