G protein signaling and vein graft intimal hyperplasia -: Reduction of intimal hyperplasia in vein grafts by a Gβγ inhibitor suggests a major role of G protein signaling in lesion development

Vein grafting results in the development of intimal hyperplasia with accompanying changes in guanine nucleotide-binding, (G) protein expression and function. Several serum mitogens that act through G protein-coupled receptors, such as lysophosphatidic acid, stimulate proliferative pathways that are dependent on the G protein beta gamma subunit (G(beta gamma))-mediated activation of p21(ras). This study examines the role of G(beta gamma) signaling in intimal hyperplasia by targeting a gene encoding a specific G(beta gamma) inhibitor in an experimental rabbit vein graft model. This inhibitor, the carboxyl terminus of the beta-adrenergic receptor kinase (beta ARK(CT)), contains a G(beta gamma)-binding domain. Vein graft intimal hyperplasia was significantly reduced by 37% (P<0.01), and physiological studies demonstrated that the normal alterations in G protein coupling phenotypically seen in this model were blocked by beta ARK(CT) treatment. Thus, it appears that G(beta gamma)-mediated pathways play a major role in intimal hyperplasia and that targeting inhibitors of G(beta gamma) signaling offers novel intraoperative therapeutic modalities to inhibit the development of vein graft intimal hyperplasia and subsequent vein graft failure.