Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle.
Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle.
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DOI：
10.1371/journal.pone.0129489
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Prakash YS
中科院分区：
文献类型：
--
作者：
Hartman W;Helan M;Smelter D;Sathish V;Thompson M;Pabelick CM;Johnson B;Prakash YS
缺氧对肺动脉结构和功能的影响是肺动脉高压等疾病的关键。最近的研究表明，称为神经营养因子的生长因子，特别是脑源性神经营养因子（BDNF），可以影响肺的结构和功能，它们在肺动脉中的作用值得进一步研究。在这项研究中，我们研究了缺氧对人BDNF的影响，以及缺氧增强人肺动脉平滑肌细胞（PASMCs）中BDNF表达和信号转导的影响。1%缺氧48 h可促进BDNF和TrkB的表达，并促进BDNF的释放。在肺动脉高压患者的动脉中，BDNF的表达和释放在基线时更高。在分离的PASMCs中，缺氧诱导的BDNF增加了细胞内对5-羟色胺的Ca 2+反应：通过HIF 1 α抑制或通过嵌合TrkB-Fc中和细胞外BDNF改变了这种效应。增强的BDNF/TrkB信号增加PASMC的存活和增殖，并减少缺氧后的凋亡。BDNF-TrkB系统在PASMCs中的表达和信号传导增强是低氧促进肺动脉结构和功能改变的潜在机制。因此，BDNF-TrkB系统可能在缺氧诱导的肺血管疾病的发病机制中起关键作用，因此是潜在的治疗靶点。
Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs). 48h of 1% hypoxia enhanced BDNF and TrkB expression, as well as release of BDNF. In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline. In isolated PASMCs, hypoxia-induced BDNF increased intracellular Ca2+ responses to serotonin: an effect altered by HIF1α inhibition or by neutralization of extracellular BDNF via chimeric TrkB-Fc. Enhanced BDNF/TrkB signaling increased PASMC survival and proliferation, and decreased apoptosis following hypoxia. Enhanced expression and signaling of the BDNF-TrkB system in PASMCs is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function. Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy.