G-PROTEIN SIGNALING AND VEIN GRAFT INTIMAL HYPERPLASIA - REDUCTION OFINTIMAL HYPERPLASIA IN VEIN GRAFTS BY A G(BETA-GAMMA) INHIBITOR SUGGESTS A MAJOR ROLE OF G-PROTEIN SIGNALING IN LESION DEVELOPMENT

Vein grafting results in the development of intimal hyperplasia with a ccompanying changes in guanine nucleotide-binding, (G) protein express ion and function. Several serum mitogens that act through G protein-co upled receptors, such as lysophosphatidic acid, stimulate proliferativ e pathways that are dependent on the G protein beta gamma subunit (G(b eta gamma))-mediated activation of p21(ras). This study examines the r ole of G(beta gamma) signaling in intimal hyperplasia by targeting a g ene encoding a specific G(beta gamma) inhibitor in an experimental rab bit vein graft model. This inhibitor, the carboxyl terminus of the bet a-adrenergic receptor kinase (beta ARK(CT)), contains a G(beta gamma)- binding domain. Vein graft intimal hyperplasia was significantly reduc ed by 37% (P<0.01), and physiological studies demonstrated that the no rmal alterations in G protein coupling phenotypically seen in this mod el were blocked by beta ARK(CT) treatment. Thus, it appears that G(bet a gamma)-mediated pathways play a major role in intimal hyperplasia an d that targeting inhibitors of G(beta gamma) signaling offers novel in traoperative therapeutic modalities to inhibit the development of vein graft intimal hyperplasia and subsequent vein graft failure.