Ponatinib attenuates experimental pulmonary arterial hypertension by modulating Wnt signaling and vasohibin-2/vasohibin-1

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• 作者：Zechun Kang¹ ; Yunxia Ji¹ ; Guanghua Zhang ; Yubei Qu ; Liang Zhang ; Wanglin Jiang ; ^{jwl518@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Ponatinib ; Endothelial-mesenchymal transition ; Pulmonary arterial hypertension ; FGF-2 ; VASH-2 ; VASH-1
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：1 March 2016
• 年：2016
• 卷：148
• 期：Complete
• 页码：1-8
• 全文大小：1399 K

文摘

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-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.

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, 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.

Significances

Our results identified a therapeutic potential of AP in PAH therapy might be modulated VASH-2/VASH-1 and the Wnt signaling.