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Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure
Journal article   Open access   Peer reviewed

Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure

Shun-Guang Wei, Yang Yu, Robert M Weiss and Robert B Felder
American journal of physiology. Heart and circulatory physiology, Vol.311(4), pp.H871-H880
10/01/2016
DOI: 10.1152/ajpheart.00362.2016
PMCID: PMC5114465
PMID: 27496879
url
https://doi.org/10.1152/ajpheart.00362.2016View
Published (Version of record) Open Access

Abstract

We previously reported that endoplasmic reticulum (ER) stress is induced in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) of heart failure (HF) rats and is reduced by inhibition of mitogen-activated protein kinase (MAPK) signaling. The present study further examined the relationship between brain MAPK signaling, ER stress, and sympathetic excitation in HF. Sham-operated (Sham) and HF rats received a 4-wk intracerebroventricular (ICV) infusion of vehicle (Veh) or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 10 μg/day). Lower mRNA levels of the ER stress biomarkers GRP78, ATF6, ATF4, and XBP-1s in the SFO and PVN of TUDCA-treated HF rats validated the efficacy of the TUDCA dose. The elevated levels of phosphorylated p44/42 and p38 MAPK in SFO and PVN of Veh-treated HF rats, compared with Sham rats, were significantly reduced in TUDCA-treated HF rats as shown by Western blot and immunofluorescent staining. Plasma norepinephrine levels were higher in Veh-treated HF rats, compared with Veh-treated Sham rats, and were significantly lower in the TUDCA-treated HF rats. TUDCA-treated HF rats also had lower mRNA levels for angiotensin converting enzyme, angiotensin II type 1 receptor, tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, and NF-κB p65, and a higher mRNA level of IκB-α, in the SFO and PVN than Veh-treated HF rats. These data suggest that ER stress contributes to the augmented sympathetic activity in HF by inducing MAPK signaling, thereby promoting inflammation and renin-angiotensin system activity in key cardiovascular regulatory regions of the brain.
 Cholagogues and Choleretics - pharmacology Tumor Necrosis Factor-alpha - genetics Heart Failure - physiopathology Male NF-KappaB Inhibitor alpha - genetics Peptidyl-Dipeptidase A - drug effects Interleukin-1beta - genetics Sympathetic Nervous System - physiopathology RNA, Messenger - metabolism Activating Transcription Factor 6 - genetics Subfornical Organ - drug effects Brain - metabolism Heat-Shock Proteins - genetics Inflammation - metabolism Receptor, Angiotensin, Type 1 - genetics Cyclooxygenase 2 - genetics p38 Mitogen-Activated Protein Kinases - metabolism Real-Time Polymerase Chain Reaction Echocardiography Signal Transduction Rats Cyclooxygenase 2 - drug effects Heart Failure - metabolism Rats, Sprague-Dawley Blotting, Western Brain - drug effects Tumor Necrosis Factor-alpha - drug effects Mitogen-Activated Protein Kinase 3 - metabolism Endoplasmic Reticulum Stress Paraventricular Hypothalamic Nucleus - metabolism Infusions, Intraventricular Mitogen-Activated Protein Kinases - drug effects Mitogen-Activated Protein Kinase 1 - metabolism Interleukin-1beta - drug effects Sympathetic Nervous System - drug effects Mitogen-Activated Protein Kinase 1 - drug effects X-Box Binding Protein 1 - drug effects Sympathetic Nervous System - metabolism Transcription Factor RelA - genetics Activating Transcription Factor 6 - drug effects Mitogen-Activated Protein Kinase 3 - drug effects Taurochenodeoxycholic Acid - pharmacology Peptidyl-Dipeptidase A - genetics Renin-Angiotensin System Receptor, Angiotensin, Type 1 - drug effects RNA, Messenger - drug effects Subfornical Organ - metabolism Heat-Shock Proteins - drug effects Activating Transcription Factor 4 - genetics Activating Transcription Factor 4 - drug effects NF-KappaB Inhibitor alpha - drug effects Paraventricular Hypothalamic Nucleus - drug effects p38 Mitogen-Activated Protein Kinases - drug effects Animals Transcription Factor RelA - drug effects X-Box Binding Protein 1 - genetics Mitogen-Activated Protein Kinases - metabolism

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