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Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis.

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Date
1999-03-30
Authors
Iaccarino, G
Smithwick, LA
Lefkowitz, RJ
Koch, WJ
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Abstract
Restenosis continues to be a major problem limiting the effectiveness of revascularization procedures. To date, the roles of heterotrimeric G proteins in the triggering of pathological vascular smooth muscle (VSM) cell proliferation have not been elucidated. betagamma subunits of heterotrimeric G proteins (Gbetagamma) are known to activate mitogen-activated protein (MAP) kinases after stimulation of certain G protein-coupled receptors; however, their relevance in VSM mitogenesis in vitro or in vivo is not known. Using adenoviral-mediated transfer of a transgene encoding a peptide inhibitor of Gbetagamma signaling (betaARKct), we evaluated the role of Gbetagamma in MAP kinase activation and proliferation in response to several mitogens, including serum, in cultured rat VSM cells. Our results include the striking finding that serum-induced proliferation of VSM cells in vitro is mediated largely via Gbetagamma. Furthermore, we studied the effects of in vivo adenoviral-mediated betaARKct gene transfer on VSM intimal hyperplasia in a rat carotid artery restenosis model. Our in vivo results demonstrated that the presence of the betaARKct in injured rat carotid arteries significantly reduced VSM intimal hyperplasia by 70%. Thus, Gbetagamma plays a critical role in physiological VSM proliferation, and targeted Gbetagamma inhibition represents a novel approach for the treatment of pathological conditions such as restenosis.
Type
Journal article
Subject
Adenoviridae
Angioplasty, Balloon
Animals
Aorta
Calcium-Calmodulin-Dependent Protein Kinases
Carotid Arteries
Carotid Stenosis
Cell Division
Cells, Cultured
Cyclic AMP-Dependent Protein Kinases
GTP-Binding Proteins
Gene Transfer Techniques
Genetic Therapy
Graft Occlusion, Vascular
Hyperplasia
Kinetics
Macromolecular Substances
Muscle, Smooth, Vascular
Rats
Recombinant Fusion Proteins
Signal Transduction
beta-Adrenergic Receptor Kinases
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https://hdl.handle.net/10161/7819
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Scholars@Duke

Lefkowitz

Robert J. Lefkowitz

The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win. Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the
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