Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig University, Giessen, Germany.
Am J Pathol. 2012 Dec;181(6):2018-29. doi: 10.1016/j.ajpath.2012.08.028. Epub 2012 Oct 8.
Pulmonary hypertension (PH) is a life-threatening disorder that is characterized by pulmonary arterial smooth muscle cell (PASMC) hyperplasia. Until now, little was been known about early changes that underlie the manifestation of PH. To characterize these early changes, we performed whole-genome microarray analysis of lungs from mice exposed to either 24 hours hypoxia or normoxia. TrkB, a member of the tyrosine kinase receptor family, and its ligand, brain-derived neurotrophic factor (BDNF), were strongly up-regulated in hypoxic mouse lungs, as well as in arteries of patients suffering from idiopathic pulmonary arterial hypertension (IPAH). BDNF stimulation of PASMC in vitro resulted in increased proliferation, TrkB and ERK1/2 phosphorylation, and nuclear translocation of the transcription factor early growth response factor 1 (Egr-1). In addition, increased Egr-1 expression was observed in idiopathic PAH lungs. The pro-proliferative effect of BDNF was attenuated by TrkB kinase inhibitor (K252a) or ERK1/2 inhibitor (U0126) pretreatment, and by knocking down Egr-1. Consequently, we have identified the BDNF-TrkB-ERK1/2 pathway as a proproliferative signaling pathway for PASMC in PH. Interference with this pathway may thus serve as an attractive reverse remodeling approach.
肺动脉高压（PH）是一种危及生命的疾病，其特征是肺动脉平滑肌细胞（PASMC）增生。直到现在，人们对导致 PH 表现的早期变化知之甚少。为了描述这些早期变化，我们对暴露于 24 小时缺氧或常氧的小鼠的肺部进行了全基因组微阵列分析。酪氨酸激酶受体家族的成员 TrkB 及其配体脑源性神经营养因子（BDNF）在缺氧小鼠的肺部以及患有特发性肺动脉高压（IPAH）的患者的动脉中强烈上调。BDNF 在体外刺激 PASMC 导致增殖增加、TrkB 和 ERK1/2 磷酸化以及转录因子早期生长反应因子 1（Egr-1）的核易位。此外，在特发性 PAH 肺中观察到 Egr-1 表达增加。BDNF 的促增殖作用可通过 TrkB 激酶抑制剂（K252a）或 ERK1/2 抑制剂（U0126）预处理以及敲低 Egr-1 来减弱。因此，我们已经确定 BDNF-TrkB-ERK1/2 途径是 PH 中 PASMC 的促增殖信号通路。因此，干扰该途径可能成为一种有吸引力的逆转重构方法。
