c-Jun N-terminal Kinase mediates prostaglandin-induced sympathoexcitation in rats with chronic heart failure by reducing GAD1 and GABRA1 expression
c-Jun N-terminal Kinase mediates prostaglandin-induced sympathoexcitation in rats with chronic heart failure by reducing GAD1 and GABRA1 expression
复制标题
c-Jun N 末端激酶通过降低 GAD1 和 GABRA1 表达介导慢性心力衰竭大鼠前列腺素诱导的交感兴奋
DOI：
10.1111/apha.12758
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Lai EY
中科院分区：
文献类型：
--
作者：
Wang RJ;Zhang W;Dong ZX;Qi YF;Hultström M;Zhou XF;Lai EY
目的前列腺素E2通过室旁核（PVN）的EP 3受体（PTGER 3）介导慢性心力衰竭（CHF）的交感兴奋。本研究的目的是探讨c-Jun N-末端激酶（JNK）在CHF大鼠室旁核γ-氨基丁酸信号通路表达调控中的作用。在麻醉大鼠中测定肾交感神经放电（RSND）和平均动脉压（MAP）对PVN输注的反应。渗透微型泵用于慢性PVN输注。结果慢性心力衰竭大鼠室旁核中JNK激活增加，谷氨酸脱羧酶1（GAD 1）和GABA A受体α 1亚单位（GABRA 1）表达减少。PVN输注PTGER 3激动剂SC-46275在假手术对照（Sham）大鼠中引起交感神经兴奋，并在CHF中进一步增加。PTGER 3拮抗剂L798106减少CHF中的交感神经兴奋和心脏功能障碍。PVN输注EP 1受体拮抗剂SC-19220、EP 2受体拮抗剂AH 6809或EP 4受体拮抗剂L-161982对交感兴奋无影响。JNK抑制剂SP 600125使CHF大鼠的交感兴奋和PVN中GAD 1和GABRA 1的表达正常化。p44/42和p38丝裂原活化蛋白激酶抑制剂PD 98059和SB 203580均不能阻止CHF时室旁核GAD 1和GABRA 1表达的下调。结论前列腺素通过上调PTGER 3激活JNK，降低GAD 1和GABRA 1在室旁核的表达，参与CHF的交感兴奋作用。
AimProstaglandin 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.MethodsChronic 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.ResultsChronic 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.ConclusionProstaglandin signalling through upregulated PTGER3 activates JNK which reduces GAD1 and GABRA1 expression in the PVN, and contributes to sympathoexcitation in CHF.