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G Protein Signaling and Vein Graft Intimal Hyperplasia

1998; Lippincott Williams & Wilkins; Volume: 18; Issue: 8 Linguagem: Inglês

10.1161/01.atv.18.8.1275

1524-4636

Mark G. Davies, Tam T. Huynh, Gregory J. Fulton, Robert J. Lefkowitz, Einar Svendsen, Per-Otto Hagen, Walter J. Koch,

Signaling Pathways in Disease

Abstract —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.