G Protein Signaling and Vein Graft Intimal Hyperplasia: Reduction of Intimal Hyperplasia in Vein Grafts by a Gbg Inhibitor
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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 (Gβγ)–mediated activation of p21ras. This study examines the role of Gβγ signaling in intimal hyperplasia by targeting a gene encoding a specific Gβγ inhibitor in an experimental rabbit vein graft model. This inhibitor, the carboxyl terminus of the β-adrenergic receptor kinase (βARKCT), contains a Gβγ-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 βARKCT treatment. Thus, it appears that Gβγ-mediated pathways play a major role in intimal hyperplasia and that targeting inhibitors of Gβγ signaling offers novel intraoperative therapeutic modalities to inhibit the development of vein graft intimal hyperplasia and subsequent vein graft failure.
carboxyl terminus of β-adrenergic receptor kinase
Published Version (Please cite this version)10.1161/01.ATV.18.8.1275
CitationDavies, M. G., T. T. T. Huynh, et al. (1998). "G Protein Signaling and Vein Graft Intimal Hyperplasia." Arteriosclerosis, Thrombosis, and Vascular Biology 18(8): 1275-1280.
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James B. Duke Distinguished Professor of Medicine
The focus of work in this laboratory is on the elucidation of the molecular properties and regulatory mechanisms controlling the function of G protein-coupled receptors. As model systems we utilize the so called adrenergic receptors for adrenaline and related molecules. The goal is to learn the general principles of signal transduction from the outside to the inside of the cell which are involved in systems as diverse as sensory perception, neuro- transmitter and hormonal signaling. Stud