Endothelin-1 driven proliferation of pulmonary arterial smooth muscle cells is c-fos dependent
Endothelin-1 driven proliferation of pulmonary arterial smooth muscle cells is c-fos dependent
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DOI：
10.1016/j.biocel.2014.06.020
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发表时间：
2014-09-01
影响因子：
4
通讯作者：
Kwapiszewska, Grazyna
中科院分区：
文献类型：
--
作者：
Biasin, Valentina;Chwalek, Karolina;Kwapiszewska, Grazyna
肺动脉高压(PH)以肺动脉平滑肌细胞(PASMC)增殖增强为特征，导致血管重构。尽管目前已有多种因素与PH发病相关，但其潜在的发病机制尚不完全清楚。在这里，我们假设已经非常短的低氧暴露可能激活了导致血管重建的分子级联反应。对仅暴露于低氧3h的小鼠肺匀浆进行的微阵列研究显示，内皮素-1(ET-1)和结缔组织生长因子(CTGF)是上调最多的基因，丝裂原活化蛋白激酶(MAPK)通路是差异最大的调节途径。这些结果的体外评估表明，ET-1而不是CTGF刺激人PASMCs增加DNA合成和增殖标记物如Ki67和细胞周期调节因子Cyclin D1的表达。此外，ET-1处理可增加细胞外信号调节激酶(ERK)依赖的c-fos表达和c-fos和c-jun转录因子的磷酸化。用siRNA沉默c-fos可抑制ET-1诱导的PASMCs增殖。免疫组织化学分析显示，与对照组相比，人特发性肺动脉高压患者、低氧暴露小鼠和野百合碱处理组大鼠肺血管壁上c-fos和c-jun的总表达和磷酸化水平较高。这些发现揭示了c-fos/c-jun参与PASMCs对ET-1的增殖反应，表明已经很短的低氧暴露导致了参与PH血管重塑的介质的调节。(C)2014爱思唯尔有限公司。保留所有权利。
Pulmonary hypertension (PH) is characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation leading to vascular remodeling. Although, multiple factors have been associated with pathogenesis of PH the underlying mechanisms are not fully understood. Here, we hypothesize that already very short exposure to hypoxia may activate molecular cascades leading to vascular remodeling.Microarray studies from lung homogenates of mice exposed to only 3 h of hypoxia revealed endothelin-1 (ET-1) and connective tissue growth factor (CTGF) as the most upregulated genes, and the mitogen-activated protein kinase (MAPK) pathway as the most differentially regulated pathway. Evaluation of these results in vitro showed that ET-1 but not CTGF stimulation of human PASMCs increased DNA synthesis and expression of proliferation markers such as Ki67 and cell cycle regulator, cyclin D1. Moreover, ET-1 treatment elevated extracellular signal-regulated kinase (Erk)-dependent c-fos expression and phosphorylation of c-fos and c-jun transcription factors. Silencing of c-fos with siRNA abrogated the ET-1-induced proliferation of PASMCs. Expression and immunohistochemical analyses revealed higher levels of total and phosphorylated c-fos and c-jun in the vessel wall of lung samples of human idiopathic pulmonary arterial hypertension patents, hypoxia-exposed mice and monocrotaline-treated rats as compared to control subjects.These findings shed the light on the involvement of c-fos/c-jun in the proliferative response of PASMCs to ET-1 indicating that already very short hypoxia exposure leads to the regulation of mediators involved in vascular remodeling underlying PH. (C) 2014 Elsevier Ltd. All rights reserved.