Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Activation of cAMP–PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury

Nature Medicine volume 3, pages 775–779 (1997)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Schwartz, S.M., Heimark, R.L. & Majesky, M.W. Developmental mechanisms underlying pathology of arteries. Physiol. Rev. 70, 1177–1209 (1990).

    Article  CAS  Google Scholar 

  2. Ross, R. The pathogenesis of atherosclerosis: A perspective for 1990. Nature 362, 801–809 (1993).

    Article  CAS  Google Scholar 

  3. Virmani, R., Farb, A. & Burke, A.P. Coronary angioplasty from the prospective of atherosclerotic plaque: Morphologic predictors of immediate success and restenosis. Am. Heart J. 127, 163–179 (1994).

    Article  CAS  Google Scholar 

  4. Clowes, A.W., Reidy, M.A. & Clowes, M.M. Mechanisms of stenosis after arterial injury. Lab. Invest. 49, 208–215 (1983).

    CAS  PubMed  Google Scholar 

  5. Clowes, A.W., Reidy, M.A. & Clowes, M.M. Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. Lab. Invest. 49, 327–333 (1983).

    CAS  PubMed  Google Scholar 

  6. Edelman, E.R., Nugent, M.A., Smith, L.T. & Karnovsky, M.J. Basic fibroblast growth factor enhances the coupling of intimal hyperplasia and proliferation of vasa vasorum in injured rat arteries. J. Clin. Invest. 89, 465–473 (1992).

    Article  CAS  Google Scholar 

  7. Jawien, A., Bowen-Pope, D.F., Lindner, V., Schwartz, S.M. & Clowes, A.W. Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J. Clin. Invest. 89, 507–511 (1992).

    Article  CAS  Google Scholar 

  8. Indolfi, C. et al. Inhibition of cellular ras prevents smooth muscle cell proliferation after vascular injury in vivo. Nature Med. 1, 541–545 (1995).

    Article  CAS  Google Scholar 

  9. Indolfi, C., Chiariello, M. & Awedimento, E.V. Selective gene therapy for proliferative disorders: Sense and antisense. Nature Med. 2, 634–635 (1996).

    Article  CAS  Google Scholar 

  10. Chang, M.V. et al. Adenovirus-mediated transfer of the herpes simplex virus thymidine kinase inhibits vascular smooth muscle cell proliferation and neointima formation following balloon angioplasty of the rat carotid artery. Mol. Med. 1, 172–181 (1995).

    Article  CAS  Google Scholar 

  11. Chang, M.V. et al. Cytostatic gene therapy for vascular proliferative disorder with a constitutively active form of the retinoblastoma gene product. Science 267 518–522 (1995).

    Article  CAS  Google Scholar 

  12. Simons, M., Edelman, E.R., DeKeyser, J.L., Langer, R. & Rosenberg, R.D. Antisense c-myb oligonucleotides inhibit intimal arterial smooth muscle cell accumulation in vivo. Nature 359, 67–70 (1992).

    Article  CAS  Google Scholar 

  13. Assender, J.W., Southgate, K.M., Hallett, M.B. & Newby, A.C. Inhibition of proliferation, but not of Ca++ mobilization, by cyclic AMP and GMP in rabbit aortic smooth muscle cells. Biochem.J. 288, 527–532 (1992).

    Article  CAS  Google Scholar 

  14. Boynton, A.L. & Whitfield, J.F. The role of cAMP in cell proliferation: A critical as sessment of the evidence. Adv. Cyclic Nudeotide Res. 15, 193–294 (1983).

    CAS  Google Scholar 

  15. Cornwell, T.L., Arnold, E., Boerth, N.J. & Lincoln, T.M. Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP. Am. J. Physiol. 36, 1405–1413 (1994).

    Article  Google Scholar 

  16. Yokozaki, H. et al. Unhydrolyzable analogues of adenosine 3′:5′-monophosphate demonstrating growth inhibition and differentiation in human cancer cells. Cancer Res. 52, 2504–2508 (1992).

    CAS  Google Scholar 

  17. Skalhegg, B.S. et al. Cyclic AMP-dependent protein kinase type I mediates the inhibitory effects of 3′ 5′-cyclic adenosine monophosphate on cell replication in human T lymphocytes. J. Biol. Chem. 267, 15707–15714 (1992).

    CAS  PubMed  Google Scholar 

  18. Sutherland, E.W. Studies on the mechanism of hormone action. Science 177, 401–408 (1972).

    Article  CAS  Google Scholar 

  19. Schwartz, D.A. & Rubin, C.S. Regulation of cAMP-dependent protein kinase subunit levels in friend erythroleukemic cells. J. Biol. Chem. 258, 777–784 (1983).

    CAS  PubMed  Google Scholar 

  20. Pastan, I.H., Johnson, G.S. & Anderson, W.B. Role of cyclic nucleotides in growth control. Annu. Rev. Biochem. 44, 491–522 (1975).

    Article  CAS  Google Scholar 

  21. Mitsuzawa, H. Increases in cell size at START caused by hyperactivation of the cAMP pathway in Saccharomyces cerevisae. Mol. Gen. Genet. 243, 158–165 (1994).

    CAS  PubMed  Google Scholar 

  22. Goodman & Gilman's The Pharmacological Basis of Therapeutics. (McGraw-Hill, NewYork, 1995).

  23. Indolfi, C. et al. Smooth muscle cell proliferation is proportional to the degree of balloon injury in a rat model of angioplasty. Circulation 92, 1230–1235 (1995).

    Article  CAS  Google Scholar 

  24. Powell, J.S. et al. Inhibition of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science 245, 186–188 (1989).

    Article  CAS  Google Scholar 

  25. Grieco, D., Porcellini, A., Avvedimento, E.V. & Gottesman, M.E. Requirement for cAMP-PKA pathway activation by M-phase–promoting factor in the transition from mitosis to interphase. Science 271, 1718–1723 (1996).

    Article  CAS  Google Scholar 

  26. Bokar, J.A. et al. Characterization of the cAMP responsive elements from the genes for the alpha-subunit of glycoprotein hormones and phosphoenolpyruvate car-boxykinase (GTP): Conserved features of nuclear protein binding between tissues and species. J. Biol. Chem. 263, 19740–19747 (1988).

    CAS  PubMed  Google Scholar 

  27. Krebs, E.G. & Beavo, J.A. Phosphorylation-dephosphorylation of enzymes. Annu. Rev. Biochem. 48, 923–959 (1979).

    Article  CAS  Google Scholar 

  28. Stryer, L. & Bourne, H.R. G proteins: a family of signal transducers [Review]. Annu. Rev. Cell. Biol. 2, 391–419 (1986).

    Article  CAS  Google Scholar 

  29. Choi, E.J., Xia, Z., Villacres, E.C. & Storm, D.R. The regulatory diversity of the mammalian adenyl cyclases [Review]. Curr. Opin. Cell Biol. 5, 269–273 (1993).

    Article  CAS  Google Scholar 

  30. Cook, S.J. & McCormick, F. Inhibition by cAMP of Ras-dependent activation of Raf. Science 262, 1069–1072 (1993).

    Article  CAS  Google Scholar 

  31. Holmes, D.R., Jr., et al. Restenosis after percutaneous transluminal coronary angioplasty: A report from the PTCA registry of the National Heart, Lung, and Blood Institute. Am. J. Cardiol. 53, 77C–81C (1984).

    Article  Google Scholar 

  32. McBride, W. et al. Restenosis after successful coronary angioplasty. N. Engl. J. Med. 318, 1734–1737 (1988).

    Article  CAS  Google Scholar 

  33. Leimgruber, P.P. et al. Restenosis after successful coronary angioplasty in patients with single-vessel disease. Circulation 73, 710–717 (1986).

    Article  CAS  Google Scholar 

  34. Guiteras Va, P. et al. Restenosis after successful percutaneous transluminal coronary angioplasty: The Montreal Heart Institute experience. Am. J. Cardiol. 60 (Suppl.), 50B–55B (1987).

    Google Scholar 

  35. The Multicenter European Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) Study Group. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: A multicenter, randomized, double-blind placebo-controlled trial. Circulation 86, 100–110 (1991).

  36. Herrmann, J.P., Hermans, W.R., Vos, J. & Serruys, P.W. Pharmacological approaches to the prevention of restenosis following angioplasty: The search for the Holy Grail? Drugs 46, 249–262 (1993).

    Article  Google Scholar 

  37. Laird, J.R. et al. Inhibition of neointimal proliferation with low-dose irradiation from a β-particle-emitting stent. Circulation 93, 529–536 (1996).

    Article  CAS  Google Scholar 

  38. Serruys, P.W. et al. Heparin-coated Palmaz-Schatz stents in human coronary arteries. Circulation 93, 412–422 (1996).

    Article  CAS  Google Scholar 

  39. Nunes, G.L. et al., Inhibition of platelet-dependent thrombosis by local delivery of heparin with a hydrogel-coated balloon. Circulation 92, 1697–1700 (1995).

    Article  CAS  Google Scholar 

  40. Rothman, A. et al. Development and characterization of a cloned rat pulmonary arterial smooth muscle cell line that maintains differentiated properties through multiple subcultures. Circulation 86, 1977–1986 (1992).

    Article  CAS  Google Scholar 

  41. Wilkinson, L. SYSTAT, the System for Statistics. (SYSTAT, Inc., Evanston, IL, 1988).

    Google Scholar 

  42. Koumi, S., Backer, C.L., Arentzen, C.E. & Sato, R. Beta adrenergic modulation of the inwardly rectifying potassium channel in isolated human ventricular myocytes: Alteration in channel response to beta adrenergic stimulation in failing human hearts. J. Clin. Invest. 96, 2870–2881 (1995).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cattedra di Cardiologia, Università degli Studi di Napoli “Federico II,”, Via S. Pansini 5, 80131, Naples, Italy

    Ciro Indolfi, Emilio Di Lorenzo, Giovanni Esposito, Antonio Rapacciuolo, Luigi Cavuto, Angela M. Stingone & Massimo Chiariello

  2. Dipartimento di Biologia e Patologia Molecolare e Cellulare, Università degli Studi di Napoli “Federico II,”, Via S. Pansini 5, 80131, Naples, Italy

    Paola Giuliano, Domenico Grieco & Ilaria Ciullo

  3. Dipartimento di Medicina Sperimentale Clinica, Facoltà di Medicina e Chirurgia di Catanzaro, Via T. Campanella, 88100, Catanzaro, Italy

    Enrico Vittorio Avvedimento

  4. Kimmel Cancer Institute, Jefferson Medical College, Bluemle Life Sciences Building, 233 South 10th Street, Philadelphia, Pennsylvania, 19107-5541, USA

    Gianluigi Condorelli

Authors
  1. Ciro Indolfi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Enrico Vittorio Avvedimento
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emilio Di Lorenzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giovanni Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Antonio Rapacciuolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paola Giuliano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Domenico Grieco
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luigi Cavuto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Angela M. Stingone
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ilaria Ciullo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gianluigi Condorelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Massimo Chiariello
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Indolfi, C., Vittorio Avvedimento, E., Lorenzo, E. et al. Activation of cAMP–PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury. Nat Med 3, 775–779 (1997). https://doi.org/10.1038/nm0797-775

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0797-775

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing