Department of Biotechnology, School of Life Science, Jilin Normal University, Siping, China.
Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China.
Acta Physiol (Oxf). 2017 Feb;219(2):494-509. doi: 10.1111/apha.12758. Epub 2016 Aug 12.
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 GABA receptor 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.
前列腺素 E2 通过室旁核 (PVN) 中的 EP3 受体 (PTGER3) 介导慢性心力衰竭 (CHF) 中的交感兴奋。本研究旨在探讨 c-Jun N 端激酶 (JNK) 在 CHF 大鼠 PVN 中 γ-氨基丁酸信号表达调控中的作用。
通过左冠状动脉结扎诱导 Wistar 大鼠慢性心力衰竭。在麻醉大鼠中测定 PVN 输注时肾交感神经放电 (RSND) 和平均动脉压 (MAP) 的反应。使用渗透微型泵进行慢性 PVN 输注。通过免疫荧光染色、实时定量 PCR 和 Western blot 检查 PTGER3 表达。
慢性心力衰竭大鼠 PVN 中 JNK 激活增加，谷氨酸脱羧酶 1 (GAD1) 和 GABA 受体 α1 亚基 (GABRA1) 表达减少。PVN 输注 PTGER3 激动剂 SC-46275 可引起假手术对照 (Sham) 大鼠交感兴奋，并进一步增加 CHF 大鼠的交感兴奋。PTGER3 拮抗剂 L798106 可减少 CHF 大鼠的交感兴奋和心脏功能障碍。PVN 输注 EP1 受体拮抗剂 SC-19220、EP2 受体拮抗剂 AH6809 或 EP4 受体拮抗剂 L-161982 对交感兴奋无影响。JNK 抑制剂 SP600125 可使 CHF 大鼠 PVN 中的交感兴奋和 GAD1 及 GABRA1 表达正常化。p44/42 和 p38 丝裂原活化蛋白激酶抑制剂 PD98059 和 SB203580 均不能防止 CHF 大鼠 PVN 中 GAD1 和 GABRA1 表达的下调。PTGER3 激动剂激活 JNK，但下调 NG108 神经元细胞中的 GAD1 和 GABRA1 表达。
通过上调的 PTGER3 介导的前列腺素信号转导激活 JNK，导致 PVN 中 GAD1 和 GABRA1 表达减少，从而导致 CHF 中的交感兴奋。
