Local Inhibition of Tyrosine Kinase Activity Markedly Attenuates the Development of Intimal Hyperplasia in Experimental Vein Grafts

Abstract

Background.Intimal hyperplasia is due to the migration and proliferation of vascular smooth muscle cells after bypass surgery. Tyrosine kinases are involved in many signal transduction pathways including cell proliferation. This study examines the effects of local treatment with the tyrosine kinase inhibitor, tyrphostin AG-51, on the formation of intimal hyperplasia in vein grafts.Materials and methods.Thirty-nine New Zealand White rabbits underwent interposition bypass grafting of the carotid artery using the jugular vein. In the first group (TKI), tyrphostin AG-51 (5 mg), dissolved in 600 μl of dimethyl sulfoxide and Ringer's lactate (2:1, v:v), was used to incubate the veinsex vivoprior to grafting and delivered locally in 2.5 ml of 30% pluronic gel after grafting. The second group (DMSO) received the same treatment but without tyrphostin. In the third group (control), tyrphostin and DMSO were omitted from the incubation and gel delivery solutions. Postoperatively, vein grafts were harvested on Day 3 for Western analysis using an antiphosphotyrosine antibody (PY-20) to assess for tyrosine kinase activity, and on Day 28 for either morphologic or contractile function studies.Results.Local application of the TKI to vein grafts resulted in a 49% reduction in intimal hyperplasia compared to DMSO-treated vein grafts (31 ± 4 μm vs. 61 ± 5 μm,P< 0.01). Treatment with DMSO alone reduced intimal hyperplasia by 28% compared to control (85 ± 4 μm,P< 0.05). The contractile responses in the DMSO and TKI-treated vein grafts were equivalent. Western analysis showed a 39-fold decrease in tyrosine phosphorylation with TKI treatment compared to control.Conclusion.This study demonstrates that local short-term treatment with TKI produces a 49% reduction in intimal hyperplasia and suggests that phosphorylation of tyrosine residues is involved in the signaling pathways leading to the development of intimal hyperplasia in vein grafts.