Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Nov 15;100(10):2611–2621. doi: 10.1172/JCI119805

Calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1C) is induced in human arterial smooth muscle cells of the synthetic, proliferative phenotype.

S D Rybalkin 1, K E Bornfeldt 1, W K Sonnenburg 1, I G Rybalkina 1, K S Kwak 1, K Hanson 1, E G Krebs 1, J A Beavo 1
PMCID: PMC508463  PMID: 9366577

Abstract

The diversity among cyclic nucleotide phosphodiesterases provides multiple mechanisms for regulation of cAMP and cGMP in the cardiovascular system. Here we report that a calmodulin-stimulated phosphodiesterase (PDE1C) is highly expressed in proliferating human arterial smooth muscle cells (SMCs) in primary culture, but not in the quiescent SMCs of intact human aorta. High levels of PDE1C were found in primary cultures of SMCs derived from explants of human newborn and adult aortas, and in SMCs cultured from severe atherosclerotic lesions. PDE1C was the major cAMP hydrolytic activity in these SMCs. PDE expression patterns in primary SMC cultures from monkey and rat aortas were different from those from human cells. In monkey, high expression of PDE1B was found, whereas PDE1C was not detected. In rat SMCs, PDE1A was the only detectable calmodulin-stimulated PDE. These findings suggest that many of the commonly used animal species may not provide good models for studying the roles of PDEs in proliferation of human SMCs. More importantly, the observation that PDE1C is induced only in proliferating SMCs suggests that it may be both an indicator of proliferation and a possible target for treatment of atherosclerosis or restenosis after angioplasty, conditions in which proliferation of arterial SMCs is negatively modulated by cyclic nucleotides.

Full Text

The Full Text of this article is available as a PDF (566.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahn H. S., Crim W., Pitts B., Sybertz E. J. Calcium-calmodulin-stimulated and cyclic-GMP-specific phosphodiesterases. Tissue distribution, drug sensitivity, and regulation of cyclic GMP levels. Adv Second Messenger Phosphoprotein Res. 1992;25:271–288. [PubMed] [Google Scholar]
  2. Assender J. W., Southgate K. M., Hallett M. B., Newby A. C. Inhibition of proliferation, but not of Ca2+ mobilization, by cyclic AMP and GMP in rabbit aortic smooth-muscle cells. Biochem J. 1992 Dec 1;288(Pt 2):527–532. doi: 10.1042/bj2880527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beavo J. A. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev. 1995 Oct;75(4):725–748. doi: 10.1152/physrev.1995.75.4.725. [DOI] [PubMed] [Google Scholar]
  4. Beltman J., Becker D. E., Butt E., Jensen G. S., Rybalkin S. D., Jastorff B., Beavo J. A. Characterization of cyclic nucleotide phosphodiesterases with cyclic GMP analogs: topology of the catalytic domains. Mol Pharmacol. 1995 Feb;47(2):330–339. [PubMed] [Google Scholar]
  5. Bentley J. K., Kadlecek A., Sherbert C. H., Seger D., Sonnenburg W. K., Charbonneau H., Novack J. P., Beavo J. A. Molecular cloning of cDNA encoding a "63"-kDa calmodulin-stimulated phosphodiesterase from bovine brain. J Biol Chem. 1992 Sep 15;267(26):18676–18682. [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  7. Cook S. J., McCormick F. Inhibition by cAMP of Ras-dependent activation of Raf. Science. 1993 Nov 12;262(5136):1069–1072. doi: 10.1126/science.7694367. [DOI] [PubMed] [Google Scholar]
  8. Eckly A. E., Lugnier C. Role of phosphodiesterases III and IV in the modulation of vascular cyclic AMP content by the NO/cyclic GMP pathway. Br J Pharmacol. 1994 Oct;113(2):445–450. doi: 10.1111/j.1476-5381.1994.tb17009.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gershlick A. H., Spriggins D., Davies S. W., Syndercombe Court Y. D., Timmins J., Timmis A. D., Rothman M. T., Layton C., Balcon R. Failure of epoprostenol (prostacyclin, PGI2) to inhibit platelet aggregation and to prevent restenosis after coronary angioplasty: results of a randomised placebo controlled trial. Br Heart J. 1994 Jan;71(1):7–15. doi: 10.1136/hrt.71.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Graves L. M., Bornfeldt K. E., Argast G. M., Krebs E. G., Kong X., Lin T. A., Lawrence J. C., Jr cAMP- and rapamycin-sensitive regulation of the association of eukaryotic initiation factor 4E and the translational regulator PHAS-I in aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7222–7226. doi: 10.1073/pnas.92.16.7222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Graves L. M., Bornfeldt K. E., Raines E. W., Potts B. C., Macdonald S. G., Ross R., Krebs E. G. Protein kinase A antagonizes platelet-derived growth factor-induced signaling by mitogen-activated protein kinase in human arterial smooth muscle cells. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10300–10304. doi: 10.1073/pnas.90.21.10300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hansen R. S., Charbonneau H., Beavo J. A. Purification of calmodulin-stimulated cyclic nucleotide phosphodiesterase by monoclonal antibody affinity chromatography. Methods Enzymol. 1988;159:543–557. doi: 10.1016/0076-6879(88)59053-5. [DOI] [PubMed] [Google Scholar]
  13. Hurwitz R. L., Hirsch K. M., Clark D. J., Holcombe V. N., Hurwitz M. Y. Induction of a calcium/calmodulin-dependent phosphodiesterase during phytohemagglutinin-stimulated lymphocyte mitogenesis. J Biol Chem. 1990 May 25;265(15):8901–8907. [PubMed] [Google Scholar]
  14. Iyengar R. Gating by cyclic AMP: expanded role for an old signaling pathway. Science. 1996 Jan 26;271(5248):461–463. doi: 10.1126/science.271.5248.461. [DOI] [PubMed] [Google Scholar]
  15. Kato J. Y., Matsuoka M., Polyak K., Massagué J., Sherr C. J. Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell. 1994 Nov 4;79(3):487–496. doi: 10.1016/0092-8674(94)90257-7. [DOI] [PubMed] [Google Scholar]
  16. Kauffman R. F., Schenck K. W., Utterback B. G., Crowe V. G., Cohen M. L. In vitro vascular relaxation by new inotropic agents: relationship to phosphodiesterase inhibition and cyclic nucleotides. J Pharmacol Exp Ther. 1987 Sep;242(3):864–872. [PubMed] [Google Scholar]
  17. Knudtson M. L., Flintoft V. F., Roth D. L., Hansen J. L., Duff H. J. Effect of short-term prostacyclin administration on restenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol. 1990 Mar 1;15(3):691–697. doi: 10.1016/0735-1097(90)90648-9. [DOI] [PubMed] [Google Scholar]
  18. Lindgren S., Rascón A., Andersson K. E., Manganiello V., Degerman E. Selective inhibition of cGMP-inhibited and cGMP-noninhibited cyclic nucleotide phosphodiesterases and relaxation of rat aorta. Biochem Pharmacol. 1991 Jul 15;42(3):545–552. doi: 10.1016/0006-2952(91)90317-x. [DOI] [PubMed] [Google Scholar]
  19. Loughney K., Martins T. J., Harris E. A., Sadhu K., Hicks J. B., Sonnenburg W. K., Beavo J. A., Ferguson K. Isolation and characterization of cDNAs corresponding to two human calcium, calmodulin-regulated, 3',5'-cyclic nucleotide phosphodiesterases. J Biol Chem. 1996 Jan 12;271(2):796–806. doi: 10.1074/jbc.271.2.796. [DOI] [PubMed] [Google Scholar]
  20. Lugnier C., Schoeffter P., Le Bec A., Strouthou E., Stoclet J. C. Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat aorta. Biochem Pharmacol. 1986 May 15;35(10):1743–1751. doi: 10.1016/0006-2952(86)90333-3. [DOI] [PubMed] [Google Scholar]
  21. McCombie W. R., Heiner C., Kelley J. M., Fitzgerald M. G., Gocayne J. D. Rapid and reliable fluorescent cycle sequencing of double-stranded templates. DNA Seq. 1992;2(5):289–296. doi: 10.3109/10425179209030961. [DOI] [PubMed] [Google Scholar]
  22. McDaniel N. L., Rembold C. M., Murphy R. A. Cyclic nucleotide dependent relaxation in vascular smooth muscle. Can J Physiol Pharmacol. 1994 Nov;72(11):1380–1385. doi: 10.1139/y94-199. [DOI] [PubMed] [Google Scholar]
  23. Miyahara M., Ito M., Itoh H., Shiraishi T., Isaka N., Konishi T., Nakano T. Isoenzymes of cyclic nucleotide phosphodiesterase in the human aorta: characterization and the effects of E4021. Eur J Pharmacol. 1995 Sep 15;284(1-2):25–33. doi: 10.1016/0014-2999(95)00355-o. [DOI] [PubMed] [Google Scholar]
  24. Monfar M., Lemon K. P., Grammer T. C., Cheatham L., Chung J., Vlahos C. J., Blenis J. Activation of pp70/85 S6 kinases in interleukin-2-responsive lymphoid cells is mediated by phosphatidylinositol 3-kinase and inhibited by cyclic AMP. Mol Cell Biol. 1995 Jan;15(1):326–337. doi: 10.1128/mcb.15.1.326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pan X., Arauz E., Krzanowski J. J., Fitzpatrick D. F., Polson J. B. Synergistic interactions between selective pharmacological inhibitors of phosphodiesterase isozyme families PDE III and PDE IV to attenuate proliferation of rat vascular smooth muscle cells. Biochem Pharmacol. 1994 Aug 17;48(4):827–835. doi: 10.1016/0006-2952(94)90062-0. [DOI] [PubMed] [Google Scholar]
  26. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993 Apr 29;362(6423):801–809. doi: 10.1038/362801a0. [DOI] [PubMed] [Google Scholar]
  27. Rybalkin S. D., Beavo J. A. Multiplicity within cyclic nucleotide phosphodiesterases. Biochem Soc Trans. 1996 Nov;24(4):1005–1009. doi: 10.1042/bst0241005. [DOI] [PubMed] [Google Scholar]
  28. Saeki T., Saito I. Isolation of cyclic nucleotide phosphodiesterase isozymes from pig aorta. Biochem Pharmacol. 1993 Sep 1;46(5):833–839. doi: 10.1016/0006-2952(93)90492-f. [DOI] [PubMed] [Google Scholar]
  29. Sonnenburg W. K., Seger D., Beavo J. A. Molecular cloning of a cDNA encoding the "61-kDa" calmodulin-stimulated cyclic nucleotide phosphodiesterase. Tissue-specific expression of structurally related isoforms. J Biol Chem. 1993 Jan 5;268(1):645–652. [PubMed] [Google Scholar]
  30. Sonnenburg W. K., Seger D., Kwak K. S., Huang J., Charbonneau H., Beavo J. A. Identification of inhibitory and calmodulin-binding domains of the PDE1A1 and PDE1A2 calmodulin-stimulated cyclic nucleotide phosphodiesterases. J Biol Chem. 1995 Dec 29;270(52):30989–31000. doi: 10.1074/jbc.270.52.30989. [DOI] [PubMed] [Google Scholar]
  31. Souness J. E., Hassall G. A., Parrott D. P. Inhibition of pig aortic smooth muscle cell DNA synthesis by selective type III and type IV cyclic AMP phosphodiesterase inhibitors. Biochem Pharmacol. 1992 Sep 1;44(5):857–866. doi: 10.1016/0006-2952(92)90116-z. [DOI] [PubMed] [Google Scholar]
  32. Thyberg J., Hedin U., Sjölund M., Palmberg L., Bottger B. A. Regulation of differentiated properties and proliferation of arterial smooth muscle cells. Arteriosclerosis. 1990 Nov-Dec;10(6):966–990. doi: 10.1161/01.atv.10.6.966. [DOI] [PubMed] [Google Scholar]
  33. Vane J. R., Botting R. M. Pharmacodynamic profile of prostacyclin. Am J Cardiol. 1995 Jan 19;75(3):3A–10A. doi: 10.1016/s0002-9149(99)80377-4. [DOI] [PubMed] [Google Scholar]
  34. Vroom M. B., Pfaffendorf M., van Wezel H. B., van Zwieten P. A. Effect of phosphodiesterase inhibitors on human arteries in vitro. Br J Anaesth. 1996 Jan;76(1):122–129. doi: 10.1093/bja/76.1.122. [DOI] [PubMed] [Google Scholar]
  35. Wu J., Dent P., Jelinek T., Wolfman A., Weber M. J., Sturgill T. W. Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3',5'-monophosphate. Science. 1993 Nov 12;262(5136):1065–1069. doi: 10.1126/science.7694366. [DOI] [PubMed] [Google Scholar]
  36. Yan C., Zhao A. Z., Bentley J. K., Beavo J. A. The calmodulin-dependent phosphodiesterase gene PDE1C encodes several functionally different splice variants in a tissue-specific manner. J Biol Chem. 1996 Oct 11;271(41):25699–25706. doi: 10.1074/jbc.271.41.25699. [DOI] [PubMed] [Google Scholar]
  37. Yan C., Zhao A. Z., Bentley J. K., Loughney K., Ferguson K., Beavo J. A. Molecular cloning and characterization of a calmodulin-dependent phosphodiesterase enriched in olfactory sensory neurons. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9677–9681. doi: 10.1073/pnas.92.21.9677. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES