Ponatinib attenuates experimental pulmonary arterial hypertension by modulating Wnt signaling and vasohibin-2/vasohibin-1
Ponatinib attenuates experimental pulmonary arterial hypertension by modulating Wnt signaling and vasohibin-2/vasohibin-1
复制标题
Ponatinib 通过调节 Wnt 信号和 vasohibin-2/vasohibin-1 减轻实验性肺动脉高压
DOI：
10.1016/j.lfs.2016.02.017
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发表时间：
2016-03-01
期刊：
影响因子：
6.1
通讯作者：
Jiang, Wanglin
中科院分区：
文献类型：
--
作者：
Kang, Zechun;Ji, Yunxia;Jiang, Wanglin
目的：肺动脉高压（PAH）时，血管生成素2/血管生成素1的比值异常，可能参与肺动脉高压时血管生成异常和血管重构。评价泊那替尼（AP）在肺动脉高压（PAH）实验模型中的药理作用，观察AP对人肺微血管内皮细胞（HPMEC）中TGF-β 1介导的内皮-间质转化（EndoMT）的影响，体外研究缺氧对人肺动脉平滑肌细胞（HPASMC）增殖和HPMEC的影响，以及体内研究对博莱霉素（BLM）诱导的PAH的影响。AP处理导致HPMEC中EndoMT减少，波形蛋白减少，而VE-钙粘蛋白增加，成纤维细胞生长因子（FGF-2）减少，血管内皮生长因子（VEGF）和血管抑制素-2（VASH-2）表达增加，而血管抑制素-1（VASH-1）表达增加，HPASMC增殖减少，wnt 5a、β-catenin和cyclin D1表达减少。AP可减轻BLM诱导的大鼠PAH，降低FGF-2、VEGF、vWF和VASH-2的表达，而增加VASH-1的表达。AP可减轻BLM诱导的大鼠肺动脉高压，病理评分降低，胶原沉积减少。此外，AP改善血流动力学和右心室肥厚。意义：我们的研究结果表明，AP在PAH治疗中的治疗潜力可能是通过调节VASH-2/VASH-1和Wnt信号转导。(C)2016 Elsevier Inc. All rights reserved.
Aims: An abnormal ratio of vasohibin-2/vasohibin-1 may be involved in the abnormal angiogenesis and vascular remodeling during pulmonary arterial hypertension (PAH).Main methods: To evaluate the pharmacological actions of Ponatinib (AP) in experimental model of PAH, the effects of AP on TGF-beta 1-mediated endothelial-mesenchymal transition (EndoMT) in human pulmonary microvascular endothelial cells (HPMEC), and the hypoxic human pulmonary artery smooth muscle cells (HPASMC) proliferation and HPMEC in vitro, and on bleomycin (BLM)-induced PAH in vivo were investigated.Key findings: AP treatment resulted in a reduction of EndoMT in HPMECs with a decrease of vimentin, whereas an increase of VE-cadherin, reduction of fibroblast growth factor (FGF-2), vascular endothelial growth factor (VEGF) and vasohibin-2 (VASH-2), whereas an increase of vasohibin-1 (VASH-1) in the hypoxic HPMEC, a reduction of the HPASMC proliferation with decreases of wnt5a, beta-catenin and cyclin D1 expression. AP ameliorated BLM-induced PAH in rats with reductions of FGF-2, VEGF, von Willebrand factor (vWF) and VASH-2 expression, whereas an increase of VASH-1 expression. AP ameliorated BLM-induced PAH in ratswith reductions of the pathological score and the collagen deposition. In addition, AP ameliorated hemodynamics and right ventricular hypertrophy.Significances: Our results identified a therapeutic potential of AP in PAH therapy might be modulated VASH-2/VASH-1 and the Wnt signaling. (C) 2016 Elsevier Inc. All rights reserved.