Kang Zechun, Ji Yunxia, Zhang Guanghua, Qu Yubei, Zhang Liang, Jiang Wanglin
The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai, PR China.
The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai, PR China.
Life Sci. 2016 Mar 1;148:1-8. doi: 10.1016/j.lfs.2016.02.017. Epub 2016 Feb 6.
An abnormal ratio of vasohibin-2/vasohibin-1 may be involved in the abnormal angiogenesis and vascular remodeling during pulmonary arterial hypertension (PAH).
To evaluate the pharmacological actions of Ponatinib (AP) in experimental model of PAH, the effects of AP on TGF-β1-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.
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, β-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 rats with reductions of the pathological score and the collagen deposition. In addition, AP ameliorated hemodynamics and right ventricular hypertrophy.
Our results identified a therapeutic potential of AP in PAH therapy might be modulated VASH-2/VASH-1 and the Wnt signaling.
血管抑制素-2/血管抑制素-1比例异常可能参与肺动脉高压（PAH）期间的异常血管生成和血管重塑。
为评估波纳替尼（AP）在PAH实验模型中的药理作用，研究了AP对人肺微血管内皮细胞（HPMEC）中转化生长因子-β1（TGF-β1）介导的内皮-间充质转化（EndoMT）、缺氧人肺动脉平滑肌细胞（HPASMC）增殖及HPMEC体外作用的影响，以及对博来霉素（BLM）诱导的体内PAH的影响。
AP处理导致HPMEC中EndoMT减少，波形蛋白减少，而血管内皮钙黏蛋白增加，成纤维细胞生长因子（FGF-2）、血管内皮生长因子（VEGF）和血管抑制素-2（VASH-2）减少，而缺氧HPMEC中血管抑制素-1（VASH-1）增加，HPASMC增殖减少，wnt5a、β-连环蛋白和细胞周期蛋白D1表达降低。AP改善了BLM诱导的大鼠PAH，FGF-2、VEGF、血管性血友病因子（vWF）和VASH-2表达降低，而VASH-1表达增加。AP改善了BLM诱导的大鼠PAH，病理评分和胶原沉积减少。此外，AP改善了血流动力学和右心室肥大。
我们的结果表明，AP在PAH治疗中的治疗潜力可能是通过调节VASH-2/VASH-1和Wnt信号通路实现的。
