Nature Medicine
3, 775 - 779 (1997)
doi:10.1038/nm0797-775
Activation of cAMP−PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injuryCiro Indolfi1, Enrico Vittorio Avvedimento3, Emilio Di Lorenzo1, Giovanni Esposito1, Antonio Rapacciuolo1, Paola Giuliano2, Domenico Grieco2, Luigi Cavuto1, Angela M. Stingone1, Ilaria Ciullo2, Gianluigi Condorelli4
& Massimo Chiariello1
1Cattedra di Cardiologia, Università degli Studi di Napoli "Federico II," Via S. Pansini 5, 80131 Naples, Italy
2Dipartimento di Biologia e Patologia Molecolare e Cellulare, Università degli Studi di Napoli "Federico II," Via S. Pansini 5, 80131 Naples, Italy
3Dipartimento di Medicina Sperimentale Clinica, Facoltà di Medicina e Chirurgia di Catanzaro, Via T. Campanella, 88100 Catanzaro, Italy
4Kimmel Cancer Institute, Jefferson Medical College, Bluemle Life Sciences Building, 233 South 10th Street, Philadelphia, Pennsylvania 19107-5541, USA Correspondence should be addressed to C.I. Injury of the arterial wall induces the formation of the neoin-tima1. This structure is generated by the growth of mitogenically activated smooth muscle cells of the arterial wall2−5. The molecular mechanism underlying the formation of the neointima involves deregulated cell growth, primarily triggered by the injury of the arterial wall6−9. The activated gene products transmitting the injury-induced mitogenic stimuli have been identified and inhibited by several means: transdominant negative expression vectors, antisense oligodeoxynucleotides, adenovirus-mediated gene transfer, antibodies and inactivating drugs8,10−12. Results of our study show that local administration of 3',5'-cyclic AMP and phosphodiesterase-inhibitor drugs (aminophylline and amrinone) to rats markedly inhibits neointima formation after balloon injury in vivo and in smooth muscle cells in vitro. The growth inhibitory effect of aminophylline was completely reversed by the inhibition of cAMP-dependent protein kinase A (PKA). These findings indicate an alternative approach to the treatment of diseases associated with injury-induced cell growth of the arterial wall, as stimulation of cAMP signaling is pharmacologically feasible in the clinical setting.
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