Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis.
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 articleSubject
AdenoviridaeAngioplasty, 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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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 Chancellor’s Distinguished Professor of Medicine and
Professor of Biochemistry and Chemistry at the Duke University Medical Center. He
has bee

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