Inhibition of Brain Mitogen-Activated Protein Kinase Signaling Reduces Central Endoplasmic Reticulum Stress and Inflammation and Sympathetic Nerve Activity in Heart Failure Rats

摘要

Mitogen-activated protein kinase (MAPK) signaling and endoplasmic reticulum (ER) stress in the brain havebeen implicated in the pathophysiology of hypertension. This study determined whether ER stress occurs in subfornicalorgan and hypothalamic paraventricular nucleus in heart failure (HF) and how MAPK signaling interacts with ERstress 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-weekintracerebroventricular infusion of inhibitors selective for p44/42 MAPK (PD98059), p38 MAPK (SB203580), orc-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 paraventricularnucleus, compared with SHAM rats, and these indicators of increased inflammation were attenuated in the HF rats treatedwith the MAPK inhibitors. Plasma norepinephrine level was higher in HF rats than in SHAM rats but was reduced inthe HF rats treated with PD98059 and SB203580. A 4-week intracerebroventricular infusion of PD98059 also improvedsome hemodynamic and anatomic indicators of left ventricular function in HF rats. These data demonstrate that ER stressincreases in the subfornical organ and paraventricular nucleus of rats with ischemia-induced HF and that inhibition of brainMAPK signaling reduces brain ER stress and inflammation and decreases sympathetic excitation in HF. An interactionbetween MAPK signaling and ER stress in cardiovascular regions of the brain may contribute to the development of HF.