Hypoxia activates Jun-N-terminal kinase, extracellular signal-regulated protein kinase, and p38 kinase in pulmonary arteries
Hypoxia activates Jun-N-terminal kinase, extracellular signal-regulated protein kinase, and p38 kinase in pulmonary arteries
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DOI：
10.1165/ajrcmb.23.5.3921
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发表时间：
2000-11-01
影响因子：
6.4
通讯作者：
Rhoades, RA
中科院分区：
文献类型：
--
作者：
Jin, NJ;Hatton, N;Rhoades, RA
慢性肺泡缺氧是肺动脉高压的主要原因。低氧诱导的肺动脉重构的细胞机制仍知之甚少。丝裂原活化蛋白激酶（MAPK）是细胞生长和增殖信号通路中的关键酶。本研究的目的是确定MAPKs，特别是jun-N-末端激酶（JNK），细胞外信号调节蛋白激酶（ERK）和p38激酶，在缺氧诱导的肺动脉重构中发挥的作用。将大鼠暴露于常压缺氧（10%O-2）1、3、7或14 d。缺氧引起肺动脉显著重构，其特征为肺动脉壁增厚，组织质量和总RNA增加。JNK，ERK和p38激酶酪氨酸磷酸化和他们的活动显着增加缺氧。JNK激活在缺氧第1天达到峰值，ERK/p38激酶激活在缺氧7天后达到峰值。免疫组化结果表明，缺氧增加磷酸化MAPK染色在大和小肺内动脉。缺氧还上调肺动脉血管内皮生长因子信使RNA（mRNA）和血小板源性生长因子受体mRNA的水平与ERK和p38激酶的激活相关的时间过程。还研究了被称为MARK下游效应物的c-jun、c-fos和p53 -1的基因表达。缺氧可上调c-fos和c-jun mRNA的表达，上调c-fos和c-jun mRNA的表达。这些数据表明，缺氧诱导的JNK激活是对缺氧应激的早期反应，ERK和p38激酶的激活似乎与缺氧诱导的肺动脉重塑有关。
Chronic alveolar hypoxia is the major cause of pulmonary hypertension. The cellular mechanisms involved in hypoxia-induced pulmonary arterial remodeling are still poorly understood. Mitogen-activated protein kinase (MAPK) is a key enzyme in the signaling pathway leading to cellular growth and proliferation. The purpose of this investigation was to determine the roles that MAPKs, specifically jun-N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), and p38 kinase, play in the hypoxia-induced pulmonary arterial remodeling. Rats were exposed to normobaric hypoxia (10% O-2) for 1, 3, 7, or 14 d. Hypoxia caused significant remodeling in the pulmonary artery characterized by thickening of pulmonary arterial wall and increases in tissue mass and total RNA. JNK, ERK, and p38 kinase tyrosine phosphorylations and their activities were significantly increased by hypoxia. JNK activation peaked at Day 1 and ERK/p38 kinase activation peaked after 7 d of hypoxia. The results from immunohistochemistry show that hypoxia increased phospho-MAPK staining in both large and small intrapulmonary arteries. Hypoxia also upregulated vascular endothelial growth factor messenger RNA (mRNA) and platelet-derived growth factor receptor mRNA levels in pulmonary artery with a time course correlated to the activation of ERK and p38 kinase. The gene expressions of c-jun, c-fos, and egr-1, known as downstream effecters of MARK, were also investigated. Hypoxia upregulated egr-1 mRNA but downregulated c-jun and c-fos mRNAs. These data suggest that hypoxia-induced activation of JNK is an early response to hypoxic stress and that activation of ERK and p38 kinase appears to be associated with hypoxia-induced pulmonary arterial remodeling.