NADPH oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogen-activated protein kinase in the rostral ventrolateral medulla
NADPH oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogen-activated protein kinase in the rostral ventrolateral medulla
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DOI：
10.1161/01.res.0000185804.79157.c0
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发表时间：
2005-10-14
影响因子：
20.1
通讯作者：
Chan, JYH
中科院分区：
文献类型：
--
作者：
Chan, SHH;Hsu, KS;Chan, JYH
交感前运动神经元位于延髓吻侧腹外侧（RVLM），是血管紧张素II （Ang II）引发其升压作用的中心部位。我们验证了NADPH氧化酶衍生的超氧阴离子（O-2）。RVLM中的-))通过激活丝裂原活化蛋白激酶（MAPK）信号通路介导Ang ii诱导的升压反应。向RVLM双侧微量注射Ang II导致腹侧髓质p38 MAPK和细胞外信号调节蛋白激酶（ERK） 1/2的血管紧张素亚型1 （AT(1)）受体依赖性磷酸化，而不是应激激活蛋白激酶/Jun n末端激酶（SAPK/JNK）。Ang ii诱导的p38 MAPK或ERK1/2磷酸化通过将NADPH氧化酶抑制剂二苯二氯铵（DPI）应用于RVLM中减弱，DPI是一种反义寡核苷酸，靶向NADPH氧化酶mRNA的p22phox或p47phox亚基，或超氧化物歧化酶模拟酶。DPI或反义p22phox或p47phox寡核苷酸处理也能减弱AT1受体依赖性的O-2（）升高。-)在RVLM由Ang II引起的腹外侧髓质产生。在功能上，Ang ii在RVLM中引发的升压反应被DPI、tempol或p38 MAPK抑制剂SB203580减弱。在RVLM神经元中，Ang II诱导的AT(1)受体介导的谷氨酸敏感自发兴奋性突触后电流频率增强也被SB203580所消除。这些结果表明NADPH氧化酶衍生的O-2(。-)是腹内外侧髓质中Ang II激活p38 MAPK或ERK1/2的基础。此外，p38 MAPK信号通路可能通过增强突触前谷氨酸向RVLM神经元的释放来介导Ang ii诱导的压力反应。
The rostral ventrolateral medulla ( RVLM), where sympathetic premotor neurons are located, is a central site via which angiotensin II ( Ang II) elicits its pressor effect. We tested the hypothesis that NADPH oxidase-derived superoxide anion ( O-2(.-)) in the RVLM mediates Ang II-induced pressor response via activation of mitogen-activated protein kinase ( MAPK) signaling pathways. Bilateral microinjection of Ang II into the RVLM resulted in an angiotensin subtype 1 ( AT(1)) receptor-dependent phosphorylation of p38 MAPK and extracellular signal-regulated protein kinase ( ERK) 1/2, but not stress-activated protein kinase/Jun N-terminal kinase ( SAPK/JNK), in the ventrolateral medulla. The Ang II-induced p38 MAPK or ERK1/2 phosphorylation was attenuated by application into the RVLM of a NADPH oxidase inhibitor, diphenyleneiodonium chloride ( DPI), an antisense oligonucleotide that targets against p22phox or p47phox subunit of NADPH oxidase mRNA, or the superoxide dismutase mimetic tempol. DPI or antisense p22phox or p47phox oligonucleotide treatment also attenuated the AT1 receptor-dependent increase in O-2(.-) production in the ventrolateral medulla elicited by Ang II at the RVLM. Functionally, Ang II-elicited pressor response in the RVLM was attenuated by DPI, tempol, or a p38 MAPK inhibitor, SB203580. The AT(1) receptor-mediated enhancement of the frequency of glutamate-sensitive spontaneous excitatory postsynaptic currents induced by Ang II in RVLM neurons was also abolished by SB203580. These results suggest that NADPH oxidase-derived O-2(.-) underlies the activation of p38 MAPK or ERK1/2 by Ang II in the ventrolateral medulla. Furthermore, the p38 MAPK signaling pathway may mediate Ang II-induced pressor response via enhancement of presynaptic release of glutamate to RVLM neurons.