Impact of HIF-1α and HIF-2α on proliferation and migration of human pulmonary artery fibroblasts in hypoxia
Impact of HIF-1α and HIF-2α on proliferation and migration of human pulmonary artery fibroblasts in hypoxia
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DOI：
10.1096/fj.05-4104fje
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发表时间：
2005-11-01
期刊：
影响因子：
4.8
通讯作者：
Hänze, J
中科院分区：
文献类型：
--
作者：
Eul, B;Rose, F;Hänze, J
肺内小动脉外膜成纤维细胞(FBPA)的增殖已被认为是肺高压和肺心病对低氧反应的早期事件。我们研究了低氧诱导转录因子(HIF)在人FBPA暴露于低氧中的作用。原代培养的FBPA细胞对缺氧有强烈的促有丝分裂反应，而细胞凋亡率明显受到抑制。此外，在低氧条件下，FBPA的迁移明显增加，但α-平滑肌肌动蛋白的表达没有明显增加。低氧诱导HIF-1α和HIF-2α显著上调(蛋白水平)，并伴有这些转录因子的核转位。通过HIF-1α和HIF-2α的mRNA和蛋白质分析以及对HIF下游靶基因的表达分析，RNA干扰技术实现了对HIF-1α和HIF-2α的特异性抑制。结果发现，缺氧诱导的FBPA增殖反应完全依赖于HIF-2α，而HIF-1α和HIF-2α干扰显著降低了FBPA的迁移反应。综上所述，HIF上调对人肺血管外膜成纤维细胞的低氧细胞反应至关重要，如增殖和迁移，模拟体内的肺动脉高压表型。注意到不同的HIF亚型依赖关系，其中HIF-2α起主导作用，这可能提供未来的干预策略。
Proliferation of adventitial fibroblasts of small intrapulmonary arteries ( FBPA) has been disclosed as an early event in the development of pulmonary hypertension and cor pulmonale in response to hypoxia. We investigated the role of hypoxia-inducible transcription factors (HIF) in human FBPA exposed to hypoxia. Primary cultures of FBPA displayed a strong mitogenic response to 24 h hypoxia, whereas the rate of apoptosis was significantly suppressed. In addition, the migration of FBPA was strongly increased under hypoxic conditions but not the expression of alpha-smooth muscle actin. Hypoxia induced a marked up-regulation ( protein level) of both HIF-1 alpha and HIF-2 alpha, alongside with nuclear translocation of these transcription factors. Specific inhibition of either HIF-1 alpha or HIF-2 alpha was achieved by RNA interference technology, as proven by HIF-1 alpha and HIF-2 alpha mRNA and protein analysis and expression analysis of HIF downstream target genes. With the use of this approach, the hypoxia-induced proliferative response of the FBPA was found to be solely HIF-2 alpha dependent, whereas the migratory response was significantly reduced by both HIF-1 alpha and HIF-2 alpha interference. In conclusion, HIF up-regulation is essential for hypoxic cellular responses in human pulmonary artery adventitial fibroblasts such as proliferation and migration, mimicking the pulmonary hypertensive phenotype in vivo. Differential HIF subtype dependency was noted, with HIF-2 alpha playing a predominant role, which may offer future intervention strategies.