title: Ponatinib attenuates experimental pulmonary arterial hypertension by modulating Wnt signaling and vasohibin-2/vasohibin-1.
abstract: OBJECTIVE
  An abnormal ratio of vasohibin-2/vasohibin-1 may be involved in the abnormal angiogenesis and vascular remodeling during pulmonary arterial hypertension (PAH).
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our results identified a therapeutic potential of AP in PAH therapy might be modulated VASH-2/VASH-1 and the Wnt signaling.
authors: 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.
authors: Zechun
authors: Z
authors: Kang
authors: 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.
authors: Yunxia
authors: Y
authors: Ji
authors: 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.
authors: Guanghua
authors: G
authors: Zhang
authors: 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.
authors: Yubei
authors: Y
authors: Qu
authors: 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.
authors: Liang
authors: L
authors: Zhang
authors: 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. Electronic address: jwl518@163.com.
authors: Wanglin
authors: W
authors: Jiang
mesh_terms: D042501:Angiogenic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*
chemical_list: D042501:Angiogenic Proteins; D018797:Cell Cycle Proteins; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C552060:VASH1 protein, rat; C000594357:VASH2 protein, mouse; C545373:ponatinib
keywords: Endothelial-mesenchymal transition; FGF-2; Ponatinib; Pulmonary arterial hypertension; VASH-1; VASH-2