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.
Keywords:
brain; endoplasmic reticulum stress; heart failure; hypothalamic paraventricular nucleus; mitogen-activated protein kinase; subfornical organ; sympathetic activity.
MeSH terms
-
Activating Transcription Factor 4 / drug effects
-
Activating Transcription Factor 4 / genetics
-
Activating Transcription Factor 6 / drug effects
-
Activating Transcription Factor 6 / genetics
-
Animals
-
Blotting, Western
-
Brain / drug effects
-
Brain / metabolism*
-
Cholagogues and Choleretics / pharmacology
-
Cyclooxygenase 2 / drug effects
-
Cyclooxygenase 2 / genetics
-
Echocardiography
-
Endoplasmic Reticulum Stress*
-
Heart Failure / metabolism*
-
Heart Failure / physiopathology
-
Heat-Shock Proteins / drug effects
-
Heat-Shock Proteins / genetics
-
Inflammation / metabolism*
-
Infusions, Intraventricular
-
Interleukin-1beta / drug effects
-
Interleukin-1beta / genetics
-
Male
-
Mitogen-Activated Protein Kinase 1 / drug effects
-
Mitogen-Activated Protein Kinase 1 / metabolism
-
Mitogen-Activated Protein Kinase 3 / drug effects
-
Mitogen-Activated Protein Kinase 3 / metabolism
-
Mitogen-Activated Protein Kinases / drug effects
-
Mitogen-Activated Protein Kinases / metabolism*
-
NF-KappaB Inhibitor alpha / drug effects
-
NF-KappaB Inhibitor alpha / genetics
-
Paraventricular Hypothalamic Nucleus / drug effects
-
Paraventricular Hypothalamic Nucleus / metabolism
-
Peptidyl-Dipeptidase A / drug effects
-
Peptidyl-Dipeptidase A / genetics
-
RNA, Messenger / drug effects
-
RNA, Messenger / metabolism
-
Rats
-
Rats, Sprague-Dawley
-
Real-Time Polymerase Chain Reaction
-
Receptor, Angiotensin, Type 1 / drug effects
-
Receptor, Angiotensin, Type 1 / genetics
-
Renin-Angiotensin System*
-
Signal Transduction
-
Subfornical Organ / drug effects
-
Subfornical Organ / metabolism
-
Sympathetic Nervous System / drug effects
-
Sympathetic Nervous System / metabolism*
-
Sympathetic Nervous System / physiopathology
-
Taurochenodeoxycholic Acid / pharmacology
-
Transcription Factor RelA / drug effects
-
Transcription Factor RelA / genetics
-
Tumor Necrosis Factor-alpha / drug effects
-
Tumor Necrosis Factor-alpha / genetics
-
X-Box Binding Protein 1 / drug effects
-
X-Box Binding Protein 1 / genetics
-
p38 Mitogen-Activated Protein Kinases / drug effects
-
p38 Mitogen-Activated Protein Kinases / metabolism
Substances
-
Activating Transcription Factor 6
-
Atf4 protein, rat
-
Atf6 protein, rat
-
Cholagogues and Choleretics
-
GRP78 protein, rat
-
Heat-Shock Proteins
-
IL1B protein, rat
-
Interleukin-1beta
-
RNA, Messenger
-
Receptor, Angiotensin, Type 1
-
Transcription Factor RelA
-
Tumor Necrosis Factor-alpha
-
X-Box Binding Protein 1
-
Xbp1 protein, rat
-
NF-KappaB Inhibitor alpha
-
Activating Transcription Factor 4
-
Taurochenodeoxycholic Acid
-
ursodoxicoltaurine
-
Cyclooxygenase 2
-
Ptgs2 protein, rat
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases
-
Peptidyl-Dipeptidase A