The p38 mitogen-activated protein kinase pathway is involved in the regulation of heme oxygenase-1 by acidic extracellular pH in aortic smooth muscle cells.
The p38 mitogen-activated protein kinase pathway is involved in the regulation of heme oxygenase-1 by acidic extracellular pH in aortic smooth muscle cells.
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p38有丝分裂原激活的蛋白激酶途径参与主动脉平滑肌细胞中酸性细胞外pH的血红素氧酶-1的调节。
DOI：
10.1002/jcb.21930
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发表时间：
2008-12-01
影响因子：
4
通讯作者：
Christou, Helen
中科院分区：
文献类型：
--
作者：
Guan, Jason;Wu, Xinqi;Arons, Elena;Christou, Helen
细胞外酸中毒（EA）通过转录和转录后机制调节血管平滑肌细胞中血红素加氧酶-1（HO-1）的表达，但涉及的信号通路尚不清楚。我们研究了有丝分裂原活化蛋白激酶（MAPK）途径在电针调节HO-1中的作用。原代大鼠主动脉平滑肌细胞暴露于EA或生理pH值。水平的总和磷酸化形式的p38，细胞外信号调节蛋白激酶1/2（ERK 1/2），c-Jun N-末端激酶/应激激活蛋白激酶（JNK 1/2），HO-1蛋白进行了评估，Western分析和HO-1 mRNA水平进行了评估，通过定量PCR。用化学抑制剂SB 203580或腺病毒感染显性阴性形式的p38α抑制p38 MAPK。用体外激酶活性测定法评价磷酸化p38 MAPK活性。通过电迁移率变动分析（EMSA）评估活化蛋白-1（AP-1）（MAPK途径的已知靶点）的结合。EA以双相方式诱导p38 MAPK磷酸化，而总p38不变。电针不改变磷酸化ERK 1/2和磷酸化JNK 1/2的水平。在诱导HO-1之前，在EA的设置中磷酸化p38 MAPK活性增加。用SB 20358或显性负性p38α寡核苷酸抑制磷酸化p38活性可消除EA对HO-1的诱导作用。EMSA显示EA组AP-1特异性结合增强。磷酸化p38活性增加之前，并可能介导HO-1诱导EA。AP-1结合的增加可能是EA对HO-1转录调控的基础。
Extracellular acidosis (EA) regulates Heme Oxygenase-1 (HO-1) expression in vascular smooth muscle cells via transcriptional and posttranscriptional mechanisms but the signaling pathways involved are not known. We examined the role of Mitogen-Activated Protein Kinase (MAPK) pathways in HO-1 regulation by EA. Primary rat aortic smooth muscle cells were exposed to EA or physiologic pH. Levels of the total and phosphorylated forms of p38, extracellular signal-regulated protein kinases1/2 (ERK1/2), c-Jun N-terminal kinases/stress-activated protein kinases (JNK1/2), and HO-1 protein were assessed by Western analysis and HO-1 mRNA levels were assessed by quantitative PCR. Inhibition of p38 MAPK was achieved with the chemical inhibitor SB203580, or adenoviral infection of a dominant-negative form of p38α. Phospho p38 MAPK activity was evaluated with an in vitro kinase activity assay. Binding of Activator Protein-1(AP-1), a known target of MAPK pathways, was assessed by Electromobility shift assay (EMSA) EA induced phosphorylation of p38 MAPK in a biphasic manner while total p38 was unchanged. EA did not alter levels of phospho ERK 1/2 and phospho JNK 1/2. There was increased phospho p38 MAPK activity in the setting of EA which preceded the induction of HO-1. Inhibition of phospho p38 activity with either SB20358 or a dominant negative p38α oligonucleotide abrogated the induction of HO-1 by EA. Increased specific binding of AP-1 in the setting of EA was shown by EMSA. Increased phospho p38 activity precedes and likely mediates HO-1 induction by EA. Increased AP-1 binding may underlie the transcriptional regulation of HO-1 by EA.
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DOI：
10.1152/ajprenal.00097.2002
发表时间：
2002-10-01
影响因子：
4.2
作者：
Feifel, E;Obexer, P;Gstraunthaler, G
通讯作者：
Gstraunthaler, G
DOI：
10.1152/ajpheart.00937.2004
发表时间：
2005-06-01
影响因子：
4.8
作者：
Christou, H;Bailey, N;Kourembanas, S
通讯作者：
Kourembanas, S
影响因子：
4.8
作者：
Elbirt, KK;Whitmarsh, AJ;Bonkovsky, HL
通讯作者：
Bonkovsky, HL
影响因子：
10.8
作者：
Liu, XM;Chapman, GB;Durante, W
通讯作者：
Durante, W
DOI：
10.1073/pnas.161272598
发表时间：
2001-07-17
影响因子：
11.1
作者：
Minamino, T;Christou, H;Kourembanas, S
通讯作者：
Kourembanas, S