Endoplasmic Reticulum (ER) Stress Induces p44/42 Mitogen‐Activated Protein Kinase (MAPK) Signaling, Inflammation and Renin‐Angiotensin System (RAS) Activity in Forebrain and Contributes to Sympathetic Nerve Activity in Heart Failure Rats

The unfolded protein response to ER stress, induced by an excessive accumulation of unfolded proteins in the ER lumen, activates a series of downstream signal transduction pathways including MAPK signaling. ER stress has been implicated in the pathophysiology of a variety of chronic disease states including diabetes mellitus, obesity and cardiovascular diseases. A role for brain ER stress in angiotensin II ‐induced hypertension in mice was recently reported. We have found that ER stress is upregulated in the subfornical organ (SFO) and hypothalamic paraventricular nucleus (PVN) of rats with ischemia‐induced heart failure (HF). We have also found that MAPK signaling is upregulated in the SFO and PVN of these HF rats and contributes to sympathetic excitation. The present study sought to determine whether brain ER stress induces p44/42 MAPK signaling and the upregulation of excitatory/inflammatory mediators in SFO and PVN and increased sympathetic nerve activity in HF. HF and SHAM rats were produced by coronary artery ligation or sham ligation, respectively. HF rats received a 4‐week intracerebroventricular (ICV) infusion (0.25 μl/hr) of vehicle (VEH) or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 10μg/day). SHAM rats received ICV VEH for 4 weeks. Total and phosphorylated p44/42 MAPK in the SFO and PVN were measured by Western blot. Immunofluorescence for phosphorylated p44/42 MAPK in the SFO and PVN was visualized by confocal microscopy. The mRNA levels of inflammatory mediators tumor necrosis factor (TNF) ‐α, interleukin (IL)‐1β, cyclooxygenase (COX) ‐2, COX‐1 and RAS components renin angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1‐R) in SFO and PVN were measured by real‐time PCR. Plasma norepinephrine (NE) was measured by ELISA. Compared with SHAM rats, VEH‐treated HF rats had higher (*p<0.05, n=6 in each group) levels of phosphorylated p44/42 MAPK (normalized to total p44/42 MAPK) in SFO and PVN. In HF rats treated with TUDCA, phosphorylated p44/42 MAPK was lower in the SFO and PVN by Western blot (~45 %*) and by immunofluorescent imaging. VEH‐treated HF rats had significantly elevated (2.2–3.6 fold*) mRNA levels for TNF‐α, IL‐1β, COX ‐2, ACE and AT1‐R in the SFO and PVN, compared with VEH‐treated SHAM rats, but these levels were markedly reduced (37–51%*, n=6 in each group) in the TUDCA‐treated HF rats. The plasma NE level (ng/ml) was higher in VEH‐treated HF (38.86 ± 2.35*) than SHAM (18.64 ± 2.59) rats; this increase was significantly attenuated in the HF rats treated with TUDCA. These data demonstrate that brain ER stress induces MAPK signaling, inflammation and RAS activity in key cardiovascular regulatory regions of the brain and contributes to the sympathetic activation in HF. Brain ER stress is a potential target for therapeutic intervention in HF. Support or Funding Information Supported by NIH RO1 HL096671 and R01 HL073986