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Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor

Title
Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor
Authors
Kwon, Sun HyungLi, LiHe, YuxiaTey, Jason Chieh ShengLi, HuanZhuplatov, IlyaKim, Seung-JungTerry, Christi M.Blumenthal, Donald K.Shiu, Yan-TingCheung, Alfred K.
Ewha Authors
김승정
SCOPUS Author ID
김승정scopus
Issue Date
2015
Journal Title
JOURNAL OF VASCULAR RESEARCH
ISSN
1018-1172JCR Link1423-0135JCR Link
Citation
vol. 52, no. 4, pp. 244 - 256
Keywords
Arteriovenous graftNeointimal hyperplasiaPerfused organ cultureSunitinibGrowth factors
Publisher
KARGER
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Background/Aims: Venous neointimal hyperplasia (NH) is the predominant cause of stenosis in hemodialysis arteriovenous grafts (AVG), but there is currently no clinically used therapy to prevent NH. Methods: A porcine AVG model was used to identify potential pharmacological targets to prevent NH. Sunitinib, a broad-spectrum tyrosine kinase inhibitor, was examined as a potential anti-NH drug utilizing in vitro and ex vivo models. Results: In an in vivo porcine model, PDGF, VEGF and their receptors PDGFR-a and VEGFR-2 were upregulated at the venous anastomosis within 2 weeks after AVG placement, with NH development by 4 weeks. Sunitinib inhibited PDGF-stimulated proliferation, migration, phosphorylation of MAPK and PI3K/Akt proteins and changes in the expression of cell-cycle regulatory proteins in vascular smooth-muscle cells as well as VEGF-stimulated endothelial cell proliferation in vitro. In an ex vivo model, significant NH was observed in porcine vein segments perfused for 12 days under pathological shear stress. Sunitinib (100 nM) inhibited NH formation, with the intima-to-lumen area ratio decreasing from 0.45 +/- 0.25 to 0.04 +/- 0.02 (p < 0.05) with treatment. Conclusion: These findings demonstrate sunitinib to be a potential NH-preventive drug as well as the utility of an ex vivo model to investigate pharmacotherapies under pathophysiological flow conditions. (C) 2016 S. Karger AG, Basel
DOI
10.1159/000442977
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의학전문대학원 > 의학과 > Journal papers
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