Hypoxia-induced proliferative response of vascular adventitial fibroblasts is dependent on G protein-mediated activation of mitogen-activated protein kinases
Hypoxia-induced proliferative response of vascular adventitial fibroblasts is dependent on G protein-mediated activation of mitogen-activated protein kinases
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DOI：
10.1074/jbc.m010690200
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发表时间：
2001-05-11
影响因子：
4.8
通讯作者：
Stenmark, KR
中科院分区：
文献类型：
--
作者：
Das, M;Bouchey, DM;Stenmark, KR
已有研究表明，低氧可刺激肺血管外膜成纤维细胞增殖。然而，参与这种生长反应的信号通路仍然不清楚。我们验证了低氧诱导成纤维细胞增殖的假设，即与血清相比，低氧诱导的成纤维细胞增殖依赖于Gα(i/o)蛋白启动的丝裂原激活蛋白(MAP)激酶的不同激活和利用模式。我们发现，在没有外源丝裂原的情况下，低氧刺激静止的成纤维细胞DNA合成和生长增加，并显著增强血清刺激的生长反应。缺氧可引起细胞外信号调节激酶(ERK)和c-jun氨基末端激酶(JNK)的一过性激活，其时程和模式与血清诱导的相似，但幅度较小。另一方面，低氧诱导的p38MAPK的激活是双相的，而血清刺激的p38MAPK的激活是短暂的，与血清刺激相比，低氧的激活幅度更大。由于PD98059、SB202190和JNK1反义寡核苷酸几乎消融了细胞的生长反应，因此ERK1/2、JNK1和p38MAPK是低氧诱导的细胞增殖所必需的，而JNK2则不是。在血清刺激的细胞中，JNK2反义寡核苷酸和PD98059对细胞的增殖有抑制作用，而SB202190则使DNA合成增加。百日咳毒素阻断Gα(I/O)介导的信号转导，显著减弱低氧诱导的DNA合成和ERK和JNK的激活，但不能抑制p38 MAP激酶的激活。我们认为，低氧本身可以作为促进牛新生外膜成纤维细胞亚群生长的刺激因素，主要是通过Gα(I/O)介导的MAP激酶复杂网络的激活，其对低氧诱导的增殖的特异性作用不同于传统的血清诱导的生长信号。
Hypoxia has been shown to act as a proliferative stimulus for adventitial fibroblasts of the pulmonary artery. The signaling pathways involved in this growth response, however, remain unclear. We tested the hypothesis that hypoxia-induced proliferation of fibroblasts would be dependent on distinct (compared with serum) activation and utilization patterns of mitogen-activated protein (MAP) kinases initiated by G alpha (i/o) proteins. We found that hypoxia stimulated increases in DNA synthesis and growth of quiescent fibroblasts in the absence of exogenous mitogens and also markedly augmented serum-stimulated growth responses. Hypoxia caused a transient activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), the time course and pattern of which was somewhat similar to that induced by serum but which was of lesser magnitude. On the other hand, hypoxia-induced activation of p38 MAP kinase was biphasic, whereas serum-stimulated activation of p38 MAP kinase was transient, and the magnitude of activation was greater for hypoxia compared with that of serum stimulation. ERK1/2, JNK1, and p38 MAP kinase but not JNK2 were necessary for hypoxia-induced proliferation because PD98059, SB202190, and JNK1 antisense oligonucleotides nearly ablated the growth response. JNK2; appeared to act as a negative modulator of hypoxia-induced growth because JNK2 antisense oligonucleotides led to an increase in DNA synthesis, In serum-stimulated cells, antisense JNK1 oligonucleotides and PD98059 had inhibitory effects on proliferation, whereas SB202190 led to an increase in DNA synthesis. Pertussis toxin, which blocks G alpha (i/o)-mediated signaling, markedly attenuated hypoxia-induced DNA synthesis and activation of ERK and JNK but not p38 MAP kinase, We conclude that hypoxia itself can act as a growth promoting stimulus for subsets of bovine neonatal adventitial fibroblasts largely through G alpha (i/o)-mediated activation of a complex network of MAP kinases whose specific contributions to hypoxia-induced proliferation differ from traditional serum-induced growth signals.