Membrane-bound protein kinase a inhibits smooth muscle cell proliferation in vitro and in vivo by amplifying cAMP-protein kinase a signals

cAMP-dependent protein kinase is anchored to discrete cellular compartments by a family of proteins, the A-kinase anchor proteins (AKAPs). We have inv estigated in vivo and in vitro the biological effects of the expression of a prototypic member of the family, AKAP75, on smooth muscle cells. In vitro expression of AKAP75 in smooth muscle cells stimulated cAMP-induced transc ription, increased the levels of the cyclin-dependent kinase-2 inhibitor p2 7(kip1), and reduced cell proliferation. In vivo expression of exogenous AK AP75 in common carotid arteries, subjected to balloon injury, significantly increased the levels of p27(kip1) and inhibited neointimal hyperplasia. Bo th the effects in smooth muscle cells in vitro and in carotid arteries in v ivo were specifically dependent on the amplification of cAMP-dependent prot ein kinase (PKA) signals by membrane-bound PKA, as indicated by selective l oss of the AKAP75 biological effects in mutants defective in the PKA anchor domain or by suppression of AKAP effects by the PKA-specific protein kinas e inhibitor. These data indicate that AKAP proteins selectively amplify cAM P-PKA signaling in vitro and in vivo and suggest a possible target for the inhibition of the neointimal hyperplasia after vascular injury.