G protein signaling and vein graft intimal hyperplasia: Reduction of intimal hyperplasia in vein grafts by a G(βγ) 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 βγ subunit (G(βγ))-mediated activation of p21(ras). This study examines the role of G(βγ) signaling in intimal hyperplasia by targeting a gene encoding a specific G(βγ) inhibitor in an experimental rabbit vein graft model. This inhibitor, the carboxyl terminus of the β-adrenergic receptor kinase (βARK(CT)), contains a G(βγ)-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 βARK(CT) treatment. Thus, it appears that G(βγ)-mediated pathways play a major role in intimal hyperplasia and that targeting inhibitors of G(βγ) signaling offers novel intraoperative therapeutic modalities to inhibit the development of vein graft intimal hyperplasia and subsequent vein graft failure.