LOCAL INHIBITION OF TYROSINE KINASE-ACTIVITY MARKEDLY ATTENUATES THE DEVELOPMENT OF INTIMAL HYPERPLASIA IN EXPERIMENTAL VEIN GRAFTS

Background. Intimal hyperplasia is due to the migration and proliferat ion of vascular smooth muscle cells after bypass surgery. Tyrosine kin ases 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), t yrphostin AG-51 (5 mg), dissolved in 600 mu l of dimethyl sulfoxide an d Ringer's lactate (2:1, v:v), was used to incubate the veins ex vivo prior to grafting and delivered locally in 2.5 mi of 30% pluronic gel after grafting. The second group (DMSO) received the same treatment bu t without tyrphostin. In the third group (control), tyrphostin and DMS O were omitted from the incubation and gel delivery solutions. Postope ratively, vein grafts were harvested on Day 3 for Western analysis usi ng an antiphosphotyrosine antibody (PY-20) to assess for tyrosine kina se activity, and on Day 28 for either morphologic or contractile funct ion studies. Results. Local application of the TKI to vein grafts resu lted in a 49% reduction in intimal hyperplasia compared to DMSO-treate d vein grafts (31 +/- 4 mu m vs. 61 +/- 5 mu m, P < 0.01). Treatment w ith DMSO alone reduced intimal hyperplasia by 28% compared to control (85 +/- 4 mu m, P < 0.05). The contractile responses in the DMSO and T KI-treated vein grafts were equivalent. Western analysis showed a 39-f old decrease in tyrosine phosphorylation with TKI treatment compared t o control. Conclusion. This study demonstrates that local short-term t reatment with TRI 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 i n vein grafts. (C) 1998 Academic Press.