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(Circulation Research. 2001;88:319.)
© 2001 American Heart Association, Inc.

Cellular Biology

Membrane-Bound Protein Kinase A Inhibits Smooth Muscle Cell Proliferation In Vitro and In Vivo by Amplifying cAMP–Protein Kinase A Signals

Ciro Indolfi¹, Eugenio Stabile¹, Carmela Coppola, Adriana Gallo, Cinzia Perrino, Giovanna Allevato, Luigi Cavuto, Daniele Torella, Emilio Di Lorenzo, Giancarlo Troncone, Antonio Feliciello, Enrico Vittorio Avvedimento, Massimo Chiariello

From the Division of Cardiology (C.I.) and Dipartimento di Medicina Sperimentale e Clinica (E.V.A.), "Magna Graecia" University, Catanzaro, and Division of Cardiology (E.S., C.C., C.P., L.C., D.T., E.D.L., M.C.) and Dipartimento di Biologia e Patologia Molecolare e Cellulare (A.G., G.A., A.F., E.V.A.), Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, University Federico II, Naples, Italy.

Correspondence to Enrico V. Avvedimento or Ciro Indolfi, Department of Patologia Molecolare e Cellulare, Centro di Endocrinologia ed Oncologia Sperimentale, CNR, Via S. Pansini, 5 80131, Naples, Italy. E-mail avvedim{at}unina.it

Abstract—cAMP-dependent protein kinase is anchored to discrete cellular compartments by a family of proteins, the A-kinase anchor proteins (AKAPs). We have investigated 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 transcription, increased the levels of the cyclin-dependent kinase-2 inhibitor p27^kip1, and reduced cell proliferation. In vivo expression of exogenous AKAP75 in common carotid arteries, subjected to balloon injury, significantly increased the levels of p27^kip1 and inhibited neointimal hyperplasia. Both the effects in smooth muscle cells in vitro and in carotid arteries in vivo were specifically dependent on the amplification of cAMP-dependent protein kinase (PKA) signals by membrane-bound PKA, as indicated by selective loss of the AKAP75 biological effects in mutants defective in the PKA anchor domain or by suppression of AKAP effects by the PKA-specific protein kinase inhibitor. These data indicate that AKAP proteins selectively amplify cAMP-PKA signaling in vitro and in vivo and suggest a possible target for the inhibition of the neointimal hyperplasia after vascular injury.

Key Words: A-kinase anchor proteins • p27 • protein kinase A • smooth muscle cells

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