Abstract 414: Inhibition of Mitogen-Activated Protein Kinase (MAPK) Signaling Ameliorates Endoplasmic Reticulum (ER) Stress, Inflammation and Sympathetic Nerve Activity in Heart Failure Rats.

Abstract

Heart failure (HF) is characterized by increased sympathetic nerve activity, driven in part by increases in brain inflammation and renin-angiotensin system activity. Angiotensin II (ANG II) and pro-inflammatory cytokines (PICs) activate neuronal MAPK signaling, which has been implicated in sympathetic activation in HF. ANG II and PICs can also activate ER stress, which plays an important role in regulating sympathetic drive and cardiovascular function in ANG II hypertension. The present study was designed to determine whether ER stress occurs in cardiovascular regions of the brain in HF, and if so how MAPK signaling interacts with ER stress. HF and SHAM (n=6) rats were produced by coronary ligation or sham ligation, respectively. HF rats received a chronic (4 wk) intracerebroventricular (ICV) infusion (0.25 μl/hr) of vehicle (Veh, n=6) or an inhibitor (0.25μg/μl, n=6 in each group) selective for p44/42 MAPK (PD98059), JNK (SP600125), or p38 MAPK (SB203580). ER stress markers (GRP78, ATF-6, P58 IPK and CHOP) and NF-κB components (NF-κB p65 and IκB-α) were measured in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) by real time PCR. Plasma norepinephrine (NE) was measured by ELISA. Compared with SHAM rats, Veh-treated HF rats had significantly (*p<0.05) higher mRNA levels for the ER stress markers in SFO (2-3 folds) and PVN (1.8-2.5 folds); these levels were lower (28-55%*) in the HF rats treated with the MAPK inhibitors, with SB203580 being most effective in SFO and PD98059 most effective in PVN. Veh-treated HF rats had higher (95 ± 11 %*) NF-κB p65 mRNA level and lower (46 ± 5 %*) IκB-α mRNA level in SFO and PVN, compared with SHAM rats; these indicators of increased inflammation did not occur in the HF rats treated with the MAPK inhibitors. The plasma NE level (ng/ml) was higher in Veh-treated HF (36.93 ± 2.60*) than SHAM (17.90 ± 2.59) rats; this increase was attenuated in the HF rats treated with PD98059 (13.64 ± 0.92*) and SB203580 (24.68 ± 2.71*). These data demonstrate that ER stress increases in the SFO and PVN of rats with ischemia-induced HF. Inhibition of brain MAPK signaling reduces brain ER stress and inflammation and decreases sympathetic excitation in HF. Brain MAPK signaling is a potential target for therapeutic intervention in HF.