TY - JOUR
T1 - Targeting G(βγ) signaling in arterial vascular smooth muscle proliferation
T2 - A novel strategy to limit restenosis
AU - Iaccarino, G.
AU - Smithwick, L. A.
AU - Lefkowitz, R. J.
AU - Koch, W. J.
PY - 1999/3/30
Y1 - 1999/3/30
N2 - 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. βγ subunits of heterotrimeric G proteins (G(βγ)) 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 G(βγ) signaling (βARKct), we evaluated the role of G(βγ) 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 G(βγ). Furthermore, we studied the effects of in vivo adenoviral- mediated βARKct gene transfer on VSM intimal hyperplasia in a rat carotid artery restenosis model. Our in vivo results demonstrated that the presence of the βARKct in injured rat carotid arteries significantly reduced VSM intimal hyperplasia by 70%. Thus, G(βγ) plays a critical role in physiological VSM proliferation, and targeted G(βγ) inhibition represents a novel approach for the treatment of pathological conditions such as restenosis.
AB - 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. βγ subunits of heterotrimeric G proteins (G(βγ)) 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 G(βγ) signaling (βARKct), we evaluated the role of G(βγ) 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 G(βγ). Furthermore, we studied the effects of in vivo adenoviral- mediated βARKct gene transfer on VSM intimal hyperplasia in a rat carotid artery restenosis model. Our in vivo results demonstrated that the presence of the βARKct in injured rat carotid arteries significantly reduced VSM intimal hyperplasia by 70%. Thus, G(βγ) plays a critical role in physiological VSM proliferation, and targeted G(βγ) inhibition represents a novel approach for the treatment of pathological conditions such as restenosis.
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U2 - 10.1073/pnas.96.7.3945
DO - 10.1073/pnas.96.7.3945
M3 - Article
C2 - 10097143
AN - SCOPUS:0033616495
VL - 96
SP - 3945
EP - 3950
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 7
ER -