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

ABSTRACT: 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.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.In an in vivo porcine model, PDGF, VEGF and their receptors PDGFR-? 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.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.

SUBMITTER: Kwon SH

PROVIDER: S-EPMC4761319 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Kwon Sun Hyung SH Li Li L He Yuxia Y Tey Chieh Sheng CS Li Huan H Zhuplatov Ilya I Kim Seung-Jung SJ Terry Christi M CM Blumenthal Donald K DK Shiu Yan-Ting YT Cheung Alfred K AK

Journal of vascular research 20150101 4

<h4>Background/aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>In an in vivo porcine model, PDGF, VEGF ...[more]

PMID: 26788996

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Project description:Background and objectivesThere is increasing evidence that microRNAs (miRNAs) play crucial roles in the regulation of neointima formation. However, the translational evidence of the role of miRNAs in dialysis vascular access is limited.Design, setting, participants, & measurementsmiRNA expression in tissues was assessed by using venous tissues harvested from ten patients on dialysis who received revision or removal surgery, and ten patients who were predialysis and received creation surgery of arteriovenous fistulas served as controls. To extend these findings, 60 patients who received angioplasty of dialysis access were enrolled and the levels of circulating miRNAs were determined before and 2 days after angioplasty. Clinical follow-up was continued monthly for 6 months. The primary outcome of angioplasty cohort was target lesion restenosis within 6 months after angioplasty.ResultsIn the surgery cohort, the expressions of miR-21, miR-130a, and miR-221 were upregulated in stenotic tissues, whereas those of miR-133 and miR-145 were downregulated. In situ hybridization revealed similar expression patterns of these miRNAs, localized predominantly in the neointima region. Twenty eight patients in the angioplasty cohort developed restenosis within 6 months. The levels of circulating miR-21, miR-130a, miR-221, miR-133, and miR-145 significantly increased 2 days after angioplasty. Kaplan-Meier plots showed that patients with an increase of miR-21 expression level >0.35 have a higher risk of patency loss (hazard ratio, 4.45; 95% confidence interval, 1.68 to 11.7). In a multivariable analysis, postangioplasty increase of miR-21 expression was independently associated with restenosis (hazard ratio, 1.20; 95% confidence interval, 1.07 to 1.35 per one unit increase of miR-21 expression level; P=0.001).ConclusionsCertain miRNAs are differentially expressed in the stenotic venous segments of dialysis accesses. An increase in blood miR-21 level with angioplasty is associated with a higher risk of restenosis.

Project description:Introduction: We recently showed that a decellularized leaf scaffold can be loaded with polylactic-co-glycolic acid (PLGA)-based rapamycin nanoparticles, this leaf patch can then inhibit venous neointimal hyperplasia in a rat inferior vena cava (IVC) venoplasty model. IL-33 plays a role in the neointimal formation after vascular injury. We hypothesized that plant leaves can absorb therapeutic drug solution and can be used as a patch with drug delivery capability, and plant leaves absorbed with IL-33 antibody can decrease venous neointimal hyperplasia in the rat IVC venoplasty model. Method: A human spiral saphenous vein (SVG) graft implanted in the popliteal vein was harvested from a patient with trauma and analyzed by immunofluorescence. Male Sprague-Dawley rats (aged 6-8 weeks) were used to create the IVC patch venoplasty model. Plant leaves absorbed with rhodamine, distilled water (control), rapamycin, IL-33, and IL-33 antibody were cut into patches (3 × 1.5 mm2) and implanted into the rat IVC. Patches were explanted at day 14 for analysis. Result: At day 14, in the patch absorbed with rhodamine group, immunofluorescence showed rhodamine fluorescence in the neointima, inside the patch, and in the adventitia. There was a significantly thinner neointima in the plant patch absorbed with rapamycin (p = 0.0231) compared to the patch absorbed with distilled water. There was a significantly large number of IL-33 (p = 0.006) and IL-1β (p = 0.012) positive cells in the human SVG neointima compared to the human great saphenous vein. In rats, there was a significantly thinner neointima, a smaller number of IL-33 (p = 0.0006) and IL-1β (p = 0.0008) positive cells in the IL-33 antibody-absorbed patch group compared to the IL-33-absorbed patch group. Conclusion: We found that the natural absorption capability of plant leaves means they can absorb drug solution efficiently and can also be used as a novel drug delivery system and venous patch. IL-33 plays a role in venous neointimal hyperplasia both in humans and rats; neutralization of IL-33 by IL-33 antibody can be a therapeutic method to decrease venous neointimal hyperplasia.

Dataset Information

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

Publications

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

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