Sun Hyung Kwon1, Li Li2, Yuxia He2, Chieh Sheng Tey2, Huan Li2, Ilya Zhuplatov2, Seung-Jung Kim3, Christi M Terry2, Donald K Blumenthal1, Yan-Ting Shiu2, Alfred K Cheung2,4. 1. Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, U.S.A. 2. Division of Nephrology & Hypertension, Department of Medicine, University of Utah, Salt Lake City, Utah, U.S.A. 3. School of Medicine, Division of Nephrology, Ewha Womans University, Seoul, South Korea. 4. Medical Service, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, U.S.A.
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-α 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.
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-α 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.
Authors: T F Franke; S I Yang; T O Chan; K Datta; A Kazlauskas; D K Morrison; D R Kaplan; P N Tsichlis Journal: Cell Date: 1995-06-02 Impact factor: 41.582
Authors: Christi M Terry; Donald K Blumenthal; Sreevalli Sikharam; Li Li; Tadashi Kuji; Steven E Kern; Alfred K Cheung Journal: Nephrol Dial Transplant Date: 2006-09-06 Impact factor: 5.992
Authors: T Kuji; T Masaki; K Goteti; L Li; S Zhuplatov; C M Terry; W Zhu; J K Leypoldt; R Rathi; D K Blumenthal; S E Kern; A K Cheung Journal: Kidney Int Date: 2006-05-03 Impact factor: 10.612