title: c-Jun N-terminal Kinase mediates prostaglandin-induced sympathoexcitation in rats with chronic heart failure by reducing GAD1 and GABRA1 expression.
abstract: Prostaglandin E2 mediates sympathoexcitation in chronic heart failure (CHF) through EP3 receptors (PTGER3) in the paraventricular nucleus (PVN). The aim of this study was to investigate the role of c-Jun N-terminal kinase (JNK) in expressional regulation of gamma-aminobutyric acid signalling in PVN in CHF rats.
  
  
  
  Chronic heart failure was induced by left coronary ligation in Wistar rats. Renal sympathetic nerve discharge (RSND) and mean arterial pressure (MAP) responses to the PVN infusion were determined in anaesthetized rats. Osmotic minipumps were used for chronic PVN infusion. PTGER3 expression was examined with immunofluorescence staining, quantitative real-time PCR and Western blot.
  
  
  
  Chronic heart failure rats had increased JNK activation and decreased glutamate decarboxylase 1 (GAD1) and GABAAreceptor alpha 1 subunit (GABRA1) expression in the PVN. PVN infusion of the PTGER3 agonist SC-46275 caused sympathoexcitation in sham-operated control (Sham) rats and increased it further in CHF. The PTGER3 antagonist L798106 reduced sympathoexcitation and cardiac dysfunction in CHF. PVN infusion of EP1 receptor antagonist SC-19220, EP2 receptor antagonist AH6809 or EP4 receptor antagonist L-161982 had no effect on sympathoexcitation. The JNK inhibitor SP600125 normalized sympathoexcitation and GAD1 and GABRA1 expression in PVN in CHF rats. Both the p44/42 and p38 mitogen-activated protein kinase inhibitors PD98059 and SB203580 could not prevent the downregulation of GAD1 and GABRA1 expression in PVN in CHF. PTGER3 agonist activated JNK but downregulated GAD1 and GABRA1 expression in NG108 neuronal cells.
  
  
  
  Prostaglandin signalling through upregulated PTGER3 activates JNK which reduces GAD1 and GABRA1 expression in the PVN, and contributes to sympathoexcitation in CHF.
authors.affiliation: Department of Biotechnology, School of Life Science, Jilin Normal University, Siping, China.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Bioscience, School of Life Science, Jilin Normal University, Siping, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.|Anesthesia and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: M
authors.identifier: 0000-0003-4675-1099
authors.initials: M
authors.lastname: Hultström
authors.affiliation: Department of Bioscience, School of Life Science, Jilin Normal University, Siping, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: E Y
authors.initials: EY
authors.lastname: Lai
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002908:Chronic Disease; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005968:Glutamate Decarboxylase / Q000096:biosynthesis*; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013564:Sympathetic Nervous System
chemical_list: C546242:Gabra1 protein, rat; C545649:Ptger3 protein, rat; D011963:Receptors, GABA-A; D058308:Receptors, Prostaglandin E, EP3 Subtype; D048031:JNK Mitogen-Activated Protein Kinases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D015232:Dinoprostone
keywords: EP3 receptor; c-Jun N-terminal kinase; chronic heart failure; paraventricular nucleus; sympathetic nerve discharge