G protein signaling and vein graft intimal hyperplasia: reduction of intimal hyperplasia in vein grafts by a Gbetagamma inhibitor suggests a major role of G protein signaling in lesion development.
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 betagamma subunit (Gbetagamma)-mediated activation of p21ras. This study examines the role of Gbetagamma signaling in intimal hyperplasia by targeting a gene encoding a specific Gbetagamma inhibitor in an experimental rabbit vein graft model. This inhibitor, the carboxyl terminus of the beta-adrenergic receptor kinase (betaARK(CT)), contains a Gbetagamma-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 betaARK(CT) treatment. Thus, it appears that Gbetagamma-mediated pathways play a major role in intimal hyperplasia and that targeting inhibitors of Gbetagamma signaling offers novel intraoperative therapeutic modalities to inhibit the development of vein graft intimal hyperplasia and subsequent vein graft failure.
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
M G
MG
Davies
T T
TT
Huynh
G J
GJ
Fulton
R J
RJ
Lefkowitz
E
E
Svendsen
P O
PO
Hagen
W J
WJ
Koch
D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D018014:Gene Transfer Techniques; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008855:Microscopy, Electron, Scanning; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D010641:Phenotype; D011817:Rabbits; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018709:Statistics, Nonparametric; D019076:Transgenes / Q000235:genetics; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D014680:Veins / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation* / Q000648:ultrastructure; D051552:beta-Adrenergic Receptor Kinases
D010446:Peptide Fragments; D011994:Recombinant Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; C114043:BARKct protein, recombinant; D051552:beta-Adrenergic Receptor Kinases; D019204:GTP-Binding Proteins