G-PROTEIN SIGNALING AND VEIN GRAFT INTIMAL HYPERPLASIA - REDUCTION OFINTIMAL HYPERPLASIA IN VEIN GRAFTS BY A G(BETA-GAMMA) INHIBITOR SUGGESTS A MAJOR ROLE OF G-PROTEIN SIGNALING IN LESION DEVELOPMENT
Mg. Davies et al., G-PROTEIN SIGNALING AND VEIN GRAFT INTIMAL HYPERPLASIA - REDUCTION OFINTIMAL HYPERPLASIA IN VEIN GRAFTS BY A G(BETA-GAMMA) INHIBITOR SUGGESTS A MAJOR ROLE OF G-PROTEIN SIGNALING IN LESION DEVELOPMENT, Arteriosclerosis, thrombosis, and vascular biology, 18(8), 1998, pp. 1275-1280
Vein grafting results in the development of intimal hyperplasia with a
ccompanying changes in guanine nucleotide-binding, (G) protein express
ion and function. Several serum mitogens that act through G protein-co
upled receptors, such as lysophosphatidic acid, stimulate proliferativ
e pathways that are dependent on the G protein beta gamma subunit (G(b
eta gamma))-mediated activation of p21(ras). This study examines the r
ole of G(beta gamma) signaling in intimal hyperplasia by targeting a g
ene encoding a specific G(beta gamma) inhibitor in an experimental rab
bit vein graft model. This inhibitor, the carboxyl terminus of the bet
a-adrenergic receptor kinase (beta ARK(CT)), contains a G(beta gamma)-
binding domain. Vein graft intimal hyperplasia was significantly reduc
ed by 37% (P<0.01), and physiological studies demonstrated that the no
rmal alterations in G protein coupling phenotypically seen in this mod
el were blocked by beta ARK(CT) treatment. Thus, it appears that G(bet
a gamma)-mediated pathways play a major role in intimal hyperplasia an
d that targeting inhibitors of G(beta gamma) signaling offers novel in
traoperative therapeutic modalities to inhibit the development of vein
graft intimal hyperplasia and subsequent vein graft failure.