© 1998 American Heart Association, Inc.
Original Contributions |
G Protein Signaling and Vein Graft Intimal Hyperplasia
Reduction of Intimal Hyperplasia in Vein Grafts by a Gß
Inhibitor Suggests a Major Role of G Protein Signaling in Lesion Development
From the Vascular Biology and Atherosclerosis Research Laboratory, Departments of Surgery (M.G.D., T.T.T.H., G.J.F., P.-O.H., W.J.K), Medicine (R.J.L.), and Biochemistry (P.-O.H.), and the Howard Hughes Research Institute (R.J.L), Duke University Medical Center, Durham, NC, and the Department of Pathology, Gades Institute, University of Bergen, Norway (E.S.).
Correspondence to Per-Otto Hagen, PhD, Duke University Medical Center, PO Box 3473, 221 Sands Bldg, Research Drive, Durham, NC 27710. E-mail hagen003{at}mc.duke.edu
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 ß subunit
(Gß)–mediated activation of p21ras. This
study examines the role of Gß signaling in intimal
hyperplasia by targeting a gene encoding a specific Gß
inhibitor in an experimental rabbit vein graft model. This
inhibitor, the carboxyl terminus of the ß-adrenergic
receptor kinase (ßARKCT), contains a
Gß-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 ßARKCT treatment. Thus, it appears that
Gß-mediated pathways play a major role in intimal
hyperplasia and that targeting inhibitors of
Gß signaling offers novel intraoperative therapeutic
modalities to inhibit the development of vein graft intimal hyperplasia
and subsequent vein graft failure.
Key Words: vein grafts • carboxyl terminus of ß-adrenergic receptor kinase • gene transfer • G proteins • intimal hyperplasia
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