Skip to main content

Advertisement

Log in

Targeting Cyclic Nucleotide Phosphodiesterase in the Heart: Therapeutic Implications

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

The second messengers, cAMP and cGMP, regulate a number of physiological processes in the myocardium, from acute contraction/relaxation to chronic gene expression and cardiac structural remodeling. Emerging evidence suggests that multiple spatiotemporally distinct pools of cyclic nucleotides can discriminate specific cellular functions from a given cyclic nucleotide-mediated signal. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing intracellular cyclic AMP and/or cyclic GMP, control the amplitude, duration, and compartmentation of cyclic nucleotide signaling. To date, more than 60 different isoforms have been described and grouped into 11 broad families (PDE1–PDE11) based on differences in their structure, kinetic and regulatory properties, as well as sensitivity to chemical inhibitors. In the heart, PDE isozymes from at least six families have been investigated. Studies using selective PDE inhibitors and/or genetically manipulated animals have demonstrated that individual PDE isozymes play distinct roles in the heart by regulating unique cyclic nucleotide signaling microdomains. Alterations of PDE activity and/or expression have also been observed in various cardiac disease models, which may contribute to disease progression. Several family-selective PDE inhibitors have been used clinically or pre-clinically for the treatment of cardiac or vascular-related diseases. In this review, we will highlight both recent advances and discrepancies relevant to cardiovascular PDE expression, pathophysiological function, and regulation. In particular, we will emphasize how these properties influence current and future development of PDE inhibitors for the treatment of pathological cardiac remodeling and dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Bender, A. T., & Beavo, J. A. (2006). Cyclic nucleotide phosphodiesterases: Molecular regulation to clinical use. Pharmacological Reviews, 58, 488–520.

    Article  CAS  PubMed  Google Scholar 

  2. Movsesian, M. A., & Alharethi, R. (2002). Inhibitors of cyclic nucleotide phosphodiesterase PDE3 as adjunct therapy for dilated cardiomyopathy. Expert Opinion on Investigational Drugs, 11, 1529–1536.

    Article  PubMed  Google Scholar 

  3. Jaski, B. E., Fifer, M. A., Wright, R. F., Braunwald, E., & Colucci, W. S. (1985). Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose–response relationships and comparison to nitroprusside. Journal of Clinical Investigation, 75, 643–649.

    Article  CAS  PubMed  Google Scholar 

  4. Galie, N., Rubin, L. J., & Simonneau, G. (2010). Phosphodiesterase inhibitors for pulmonary hypertension. The New England Journal of Medicine, 362, 559–560, author reply 560.

    Google Scholar 

  5. Ghofrani, H. A., Osterloh, I. H., & Grimminger, F. (2006). Sildenafil: From angina to erectile dysfunction to pulmonary hypertension and beyond. Nature Reviews. Drug Discovery, 5, 689–702.

    Article  CAS  PubMed  Google Scholar 

  6. Kumar, P., Francis, G. S., & Tang, W. H. (2009). Phosphodiesterase 5 inhibition in heart failure: Mechanisms and clinical implications. Nature Reviews Cardiology, 6, 349–355.

    Article  CAS  PubMed  Google Scholar 

  7. Kukreja, R. C., Salloum, F., Das, A., Ockaili, R., Yin, C., Bremer, Y. A., et al. (2005). Pharmacological preconditioning with sildenafil: Basic mechanisms and clinical implications. Vascular Pharmacology, 42, 219–232.

    Article  CAS  PubMed  Google Scholar 

  8. Sonnenburg, W. K., Seger, D., & Beavo, J. A. (1993). Molecular cloning of a cDNA encoding the “61-kDa” calmodulin-stimulated cyclic nucleotide phosphodiesterase. Tissue-specific expression of structurally related isoforms. The Journal of Biological Chemistry, 268, 645–652.

    CAS  PubMed  Google Scholar 

  9. Yan, C., Kim, D., Aizawa, T., & Berk, B. C. (2003). Functional interplay between angiotensin II and nitric oxide: Cyclic GMP as a key mediator. Arteriosclerosis, Thrombosis, and Vascular Biology, 23, 26–36.

    Article  CAS  PubMed  Google Scholar 

  10. Nagel, D. J., Aizawa, T., Jeon, K. I., Liu, W., Mohan, A., Wei, H., et al. (2006). Role of nuclear Ca2+/calmodulin-stimulated phosphodiesterase 1A in vascular smooth muscle cell growth and survival. Circulation Research, 98, 777–784.

    Article  CAS  PubMed  Google Scholar 

  11. Bender, A. T., & Beavo, J. A. (2006). PDE1B2 regulates cGMP and a subset of the phenotypic characteristics acquired upon macrophage differentiation from a monocyte. Proceedings of the National Academy of Sciences of the United States of America, 103, 460–465.

    Article  CAS  PubMed  Google Scholar 

  12. Miller, C. L., Oikawa, M., Cai, Y., Wojtovich, A. P., Nagel, D. J., Xu, X., et al. (2009). Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy. Circulation Research, 105, 956–964.

    Article  CAS  PubMed  Google Scholar 

  13. Rybalkin, S. D., Rybalkina, I., Beavo, J. A., & Bornfeldt, K. E. (2002). Cyclic nucleotide phosphodiesterase 1C promotes human arterial smooth muscle cell proliferation. Circulation Research, 90, 151–157.

    Article  CAS  PubMed  Google Scholar 

  14. Han, P., Werber, J., Surana, M., Fleischer, N., & Michaeli, T. (1999). The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion. The Journal of Biological Chemistry, 274, 22337–22344.

    Article  CAS  PubMed  Google Scholar 

  15. Dunkern, T. R., & Hatzelmann, A. (2007). Characterization of inhibitors of phosphodiesterase 1C on a human cellular system. The FEBS Journal, 274, 4812–4824.

    Article  CAS  PubMed  Google Scholar 

  16. Wallis, R. M., Corbin, J. D., Francis, S. H., & Ellis, P. (1999). Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. The American Journal of Cardiology, 83, 3C–12C.

    Article  CAS  PubMed  Google Scholar 

  17. Vandeput, F., Wolda, S. L., Krall, J., Hambleton, R., Uher, L., McCaw, K. N., et al. (2007). Cyclic nucleotide phosphodiesterase PDE1C1 in human cardiac myocytes. The Journal of Biological Chemistry, 282, 32749–32757.

    Article  CAS  PubMed  Google Scholar 

  18. Loughney, K., Martins, T. J., Harris, E. A., Sadhu, K., Hicks, J. B., Sonnenburg, W. K., et al. (1996). Isolation and characterization of cDNAs corresponding to two human calcium, calmodulin-regulated, 3′,5′-cyclic nucleotide phosphodiesterases. The Journal of Biological Chemistry, 271, 796–806.

    Article  CAS  PubMed  Google Scholar 

  19. Clapham, J. C., & Wilderspin, A. F. (2001). Cloning of dog heart PDE1A—A first detailed characterization at the molecular level in this species. Gene, 268, 165–171.

    Article  CAS  PubMed  Google Scholar 

  20. Yanaka, N., Kurosawa, Y., Minami, K., Kawai, E., & Omori, K. (2003). cGMP-phosphodiesterase activity is up-regulated in response to pressure overload of rat ventricles. Bioscience, Biotechnology, and Biochemistry, 67, 973–979.

    Article  CAS  PubMed  Google Scholar 

  21. Bode, D. C., Kanter, J. R., & Brunton, L. L. (1991). Cellular distribution of phosphodiesterase isoforms in rat cardiac tissue. Circulation Research, 68, 1070–1079.

    CAS  PubMed  Google Scholar 

  22. Lukowski, R., Rybalkin, S. D., Loga, F., Leiss, V., Beavo, J. A., & Hofmann, F. (2010). Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes. Proceedings of the National Academy of Sciences of the United States of America, 107, 5646–5651.

    Article  CAS  PubMed  Google Scholar 

  23. Patrucco, E., Albergine, M. S., Santana, L. F., & Beavo, J. A. (2010). Phosphodiesterase 8A (PDE8A) regulates excitation–contraction coupling in ventricular myocytes. Journal of Molecular and Cell Cardiology, 49, 330–333.

    Article  CAS  Google Scholar 

  24. Schermuly, R. T., Pullamsetti, S. S., Kwapiszewska, G., Dumitrascu, R., Tian, X., Weissmann, N., et al. (2007). Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: Target for reverse-remodeling therapy. Circulation, 115, 2331–2339.

    Article  CAS  PubMed  Google Scholar 

  25. Dittrich, M., Jurevicius, J., Georget, M., Rochais, F., Fleischmann, B., Hescheler, J., et al. (2001). Local response of L-type Ca(2+) current to nitric oxide in frog ventricular myocytes. Journal de Physiologie, 534, 109–121.

    Article  CAS  Google Scholar 

  26. Mery, P. F., Pavoine, C., Belhassen, L., Pecker, F., & Fischmeister, R. (1993). Nitric oxide regulates cardiac Ca2+ current. Involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activation. The Journal of Biological Chemistry, 268, 26286–26295.

    CAS  PubMed  Google Scholar 

  27. Rivet-Bastide, M., Vandecasteele, G., Hatem, S., Verde, I., Benardeau, A., Mercadier, J. J., et al. (1997). cGMP-stimulated cyclic nucleotide phosphodiesterase regulates the basal calcium current in human atrial myocytes. Journal of Clinical Investigation, 99, 2710–2718.

    Article  CAS  PubMed  Google Scholar 

  28. Mery, P. F., Lohmann, S. M., Walter, U., & Fischmeister, R. (1991). Ca2+ current is regulated by cyclic GMP-dependent protein kinase in mammalian cardiac myocytes. Proceedings of the National Academy of Sciences of the United States of America, 88, 1197–1201.

    Article  CAS  PubMed  Google Scholar 

  29. Fischmeister, R., Castro, L., Abi-Gerges, A., Rochais, F., & Vandecasteele, G. (2005). Species- and tissue-dependent effects of NO and cyclic GMP on cardiac ion channels. Comparative Biochemistry and Physiology. Part A: Molecular & Integrative Physiology, 142, 136–143.

    Article  Google Scholar 

  30. Mongillo, M., Tocchetti, C. G., Terrin, A., Lissandron, V., Cheung, Y. F., Dostmann, W. R., et al. (2006). Compartmentalized phosphodiesterase-2 activity blunts beta-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway. Circulation Research, 98, 226–234.

    Article  CAS  PubMed  Google Scholar 

  31. Castro, L. R., Verde, I., Cooper, D. M., & Fischmeister, R. (2006). Cyclic guanosine monophosphate compartmentation in rat cardiac myocytes. Circulation, 113, 2221–2228.

    Article  CAS  PubMed  Google Scholar 

  32. Diebold, I., Djordjevic, T., Petry, A., Hatzelmann, A., Tenor, H., Hess, J., et al. (2009). Phosphodiesterase 2 mediates redox-sensitive endothelial cell proliferation and angiogenesis by thrombin via Rac1 and NADPH oxidase 2. Circulation Research, 104, 1169–1177.

    Article  CAS  PubMed  Google Scholar 

  33. Shakur, Y., Holst, L. S., Landstrom, T. R., Movsesian, M., Degerman, E., & Manganiello, V. (2001). Regulation and function of the cyclic nucleotide phosphodiesterase (PDE3) gene family. Progress in Nucleic Acid Research and Molecular Biology, 66, 241–277.

    Article  CAS  PubMed  Google Scholar 

  34. Choi, Y. H., Ekholm, D., Krall, J., Ahmad, F., Degerman, E., Manganiello, V. C., et al. (2001). Identification of a novel isoform of the cyclic-nucleotide phosphodiesterase PDE3A expressed in vascular smooth-muscle myocytes. The Biochemical Journal, 353, 41–50.

    Article  CAS  PubMed  Google Scholar 

  35. Liu, Y., Shakur, Y., Yoshitake, M., Kambayashi, & Ji, J. (2001). Cilostazol (pletal): A dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine uptake. Cardiovascular Drug Reviews, 19, 369–386.

    Article  CAS  PubMed  Google Scholar 

  36. Patrucco, E., Notte, A., Barberis, L., Selvetella, G., Maffei, A., Brancaccio, M., et al. (2004). PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell, 118, 375–387.

    Article  CAS  PubMed  Google Scholar 

  37. Voigt, P., Dorner, M. B., & Schaefer, M. (2006). Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase gamma that is highly expressed in heart and interacts with PDE3B. The Journal of Biological Chemistry, 281, 9977–9986.

    Article  CAS  PubMed  Google Scholar 

  38. Sun, B., Li, H., Shakur, Y., Hensley, J., Hockman, S., Kambayashi, J., et al. (2007). Role of phosphodiesterase type 3A and 3B in regulating platelet and cardiac function using subtype-selective knockout mice. Cellular Signalling, 19, 1765–1771.

    Article  CAS  PubMed  Google Scholar 

  39. Benotti, J. R., Grossman, W., Braunwald, E., Davolos, D. D., & Alousi, A. A. (1978). Hemodynamic assessment of amrinone. A new inotropic agent. The New England Journal of Medicine, 299, 1373–1377.

    Article  CAS  PubMed  Google Scholar 

  40. Baim, D. S., McDowell, A. V., Cherniles, J., Monrad, E. S., Parker, J. A., Edelson, J., et al. (1983). Evaluation of a new bipyridine inotropic agent—milrinone—in patients with severe congestive heart failure. The New England Journal of Medicine, 309, 748–756.

    Article  CAS  PubMed  Google Scholar 

  41. DiBianco, R., Shabetai, R., Kostuk, W., Moran, J., Schlant, R. C., & Wright, R. (1989). A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. The New England Journal of Medicine, 320, 677–683.

    Article  CAS  PubMed  Google Scholar 

  42. Xamoterol in severe heart failure. (1990). The Xamoterol in severe heart failure study group. Lancet, 336, 1–6.

    Article  Google Scholar 

  43. Oliva, F., Latini, R., Politi, A., Staszewsky, L., Maggioni, A. P., Nicolis, E., et al. (1999). Intermittent 6-month low-dose dobutamine infusion in severe heart failure: DICE multicenter trial. American Heart Journal, 138, 247–253.

    Article  CAS  PubMed  Google Scholar 

  44. Ding, B., Abe, J., Wei, H., Huang, Q., Walsh, R. A., Molina, C. A., et al. (2005). Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: Implication in heart failure. Circulation, 111, 2469–2476.

    Article  CAS  PubMed  Google Scholar 

  45. Ding, B., Abe, J., Wei, H., Xu, H., Che, W., Aizawa, T., et al. (2005). A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 102, 14771–14776.

    Article  CAS  PubMed  Google Scholar 

  46. Tomita, H., Nazmy, M., Kajimoto, K., Yehia, G., Molina, C. A., & Sadoshima, J. (2003). Inducible cAMP early repressor (ICER) is a negative-feedback regulator of cardiac hypertrophy and an important mediator of cardiac myocyte apoptosis in response to beta-adrenergic receptor stimulation. Circulation Research, 93, 12–22.

    Article  CAS  PubMed  Google Scholar 

  47. Mioduszewska, B., Jaworski, J., & Kaczmarek, L. (2003). Inducible cAMP early repressor (ICER) in the nervous system—A transcriptional regulator of neuronal plasticity and programmed cell death. Journal of Neurochemistry, 87, 1313–1320.

    Article  CAS  PubMed  Google Scholar 

  48. Jaworski, J., Mioduszewska, B., Sanchez-Capelo, A., Figiel, I., Habas, A., Gozdz, A., et al. (2003). Inducible cAMP early repressor, an endogenous antagonist of cAMP responsive element-binding protein, evokes neuronal apoptosis in vitro. The Journal of Neuroscience, 23, 4519–4526.

    CAS  PubMed  Google Scholar 

  49. Yan, C., Miller, C. L., & Abe, J. (2007). Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart. Circulation Research, 100, 489–501.

    Article  CAS  PubMed  Google Scholar 

  50. Packer, M., Carver, J. R., Rodeheffer, R. J., Ivanhoe, R. J., DiBianco, R., Zeldis, S. M., et al. (1991). Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. The New England Journal of Medicine, 325, 1468–1475.

    Article  CAS  PubMed  Google Scholar 

  51. Yan, C., Ding, B., Shishido, T., Woo, C. H., Itoh, S., Jeon, K. I., et al. (2007). Activation of extracellular signal-regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop. Circulation Research, 100, 510–519.

    Article  CAS  PubMed  Google Scholar 

  52. Abi-Gerges, A., Richter, W., Lefebvre, F., Mateo, P., Varin, A., Heymes, C., et al. (2009). Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on beta-adrenergic cAMP signals. Circulation Research, 105, 784–792.

    Article  CAS  PubMed  Google Scholar 

  53. Ma, D., Fu, L., Shen, J., Zhou, P., Gao, Y., Xie, R., et al. (2009). Interventional effect of valsartan on expression of inducible cAMP early repressor and phosphodiesterase 3A in rats after myocardial infarction. European Journal of Pharmacology, 602, 348–354.

    Article  CAS  PubMed  Google Scholar 

  54. Lehnart, S. E., Wehrens, X. H., Reiken, S., Warrier, S., Belevych, A. E., Harvey, R. D., et al. (2005). Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell, 123, 25–35.

    Article  CAS  PubMed  Google Scholar 

  55. Wehrens, X. H., Lehnart, S. E., Huang, F., Vest, J. A., Reiken, S. R., Mohler, P. J., et al. (2003). FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell, 113, 829–840.

    Article  CAS  PubMed  Google Scholar 

  56. Houslay, M. D., Baillie, G. S., & Maurice, D. H. (2007). cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: A molecular toolbox for generating compartmentalized cAMP signaling. Circulation Research, 100, 950–966.

    Article  CAS  PubMed  Google Scholar 

  57. Kukreja, R. C., Ockaili, R., Salloum, F., Yin, C., Hawkins, J., Das, A., et al. (2004). Cardioprotection with phosphodiesterase-5 inhibition—A novel preconditioning strategy. Journal of Molecular and Cellular Cardiology, 36, 165–173.

    Article  CAS  PubMed  Google Scholar 

  58. Kass, D. A., Champion, H. C., & Beavo, J. A. (2007). Phosphodiesterase type 5: Expanding roles in cardiovascular regulation. Circulation Research, 101, 1084–1095.

    Article  CAS  PubMed  Google Scholar 

  59. Salloum, F., Yin, C., Xi, L., & Kukreja, R. C. (2003). Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart. Circulation Research, 92, 595–597.

    Article  CAS  PubMed  Google Scholar 

  60. Das, A., Xi, L., & Kukreja, R. C. (2005). Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. The Journal of Biological Chemistry, 280, 12944–12955.

    Article  CAS  PubMed  Google Scholar 

  61. Fisher, P. W., Salloum, F., Das, A., Hyder, H., & Kukreja, R. C. (2005). Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation, 111, 1601–1610.

    Article  CAS  PubMed  Google Scholar 

  62. Ockaili, R., Salloum, F., Hawkins, J., & Kukreja, R. C. (2002). Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K(ATP) channels in rabbits. American Journal of Physiology. Heart and Circulatory Physiology, 283, H1263–1269.

    CAS  PubMed  Google Scholar 

  63. Takimoto, E., Koitabashi, N., Hsu, S., Ketner, E. A., Zhang, M., Nagayama, T., et al. (2009). Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. Journal of Clinical Investigation, 119, 408–420.

    CAS  PubMed  Google Scholar 

  64. Corbin, J., Rannels, S., Neal, D., Chang, P., Grimes, K., Beasley, A., et al. (2003). Sildenafil citrate does not affect cardiac contractility in human or dog heart. Current Medical Research and Opinion, 19, 747–752.

    Article  CAS  PubMed  Google Scholar 

  65. Vandeput, F., Krall, J., Ockaili, R., Salloum, F. N., Florio, V., Corbin, J. D., et al. (2009). cGMP-hydrolytic activity and its inhibition by sildenafil in normal and failing human and mouse myocardium. The Journal of Pharmacology and Experimental Therapeutics, 330, 884–891.

    Article  CAS  PubMed  Google Scholar 

  66. Zhang, M., Koitabashi, N., Nagayama, T., Rambaran, R., Feng, N., Takimoto, E., et al. (2008). Expression, activity, and pro-hypertrophic effects of PDE5A in cardiac myocytes. Cellular Signalling, 20, 2231–2236.

    Article  CAS  PubMed  Google Scholar 

  67. Schermuly, R. T., Inholte, C., Ghofrani, H. A., Gall, H., Weissmann, N., Weidenbach, A., et al. (2005). Lung vasodilatory response to inhaled iloprost in experimental pulmonary hypertension: Amplification by different type phosphodiesterase inhibitors. Respiratory Research, 6, 76.

    Article  PubMed  Google Scholar 

  68. Paul, G. A., Gibbs, J. S., Boobis, A. R., Abbas, A., & Wilkins, M. R. (2005). Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. British Journal of Clinical Pharmacology, 60, 107–112.

    Article  CAS  PubMed  Google Scholar 

  69. Borlaug, B. A., Melenovsky, V., Marhin, T., Fitzgerald, P., & Kass, D. A. (2005). Sildenafil inhibits beta-adrenergic-stimulated cardiac contractility in humans. Circulation, 112, 2642–2649.

    Article  CAS  PubMed  Google Scholar 

  70. Takimoto, E., Champion, H. C., Li, M., Belardi, D., Ren, S., Rodriguez, E. R., et al. (2005). Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Natural Medicines, 11, 214–222.

    Article  CAS  Google Scholar 

  71. Salloum, F. N., Chau, V. Q., Hoke, N. N., Abbate, A., Varma, A., Ockaili, R. A., et al. (2009). Phosphodiesterase-5 inhibitor, tadalafil, protects against myocardial ischemia/reperfusion through protein-kinase G-dependent generation of hydrogen sulfide. Circulation, 120, S31–S36.

    Article  CAS  PubMed  Google Scholar 

  72. Pokreisz, P., Vandenwijngaert, S., Bito, V., Van den Bergh, A., Lenaerts, I., Busch, C., et al. (2009). Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice. Circulation, 119, 408–416.

    Article  CAS  PubMed  Google Scholar 

  73. Nagendran, J., Archer, S. L., Soliman, D., Gurtu, V., Moudgil, R., Haromy, A., et al. (2007). Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation, 116, 238–248.

    Article  CAS  PubMed  Google Scholar 

  74. Traverse, J. H., Chen, Y. J., Du, R., & Bache, R. J. (2000). Cyclic nucleotide phosphodiesterase type 5 activity limits blood flow to hypoperfused myocardium during exercise. Circulation, 102, 2997–3002.

    CAS  PubMed  Google Scholar 

  75. Jackson, G. (2001). Phosphodiesterase 5 inhibition: Effects on the coronary vasculature. International Journal of Clinical Practice, 55, 183–188.

    CAS  PubMed  Google Scholar 

  76. Brindis, R. G., & Kloner, R. A. (2003). Sildenafil in patients with cardiovascular disease. The American Journal of Cardiology, 92, 26M–36M.

    Article  CAS  PubMed  Google Scholar 

  77. Sahara, M., Sata, M., Morita, T., Nakajima, T., Hirata, Y., & Nagai, R. (2010). A phosphodiesterase-5 inhibitor vardenafil enhances angiogenesis through a protein kinase G-dependent hypoxia-inducible factor-1/vascular endothelial growth factor pathway. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 1315–1324.

    Article  CAS  PubMed  Google Scholar 

  78. Pyriochou, A., Zhou, Z., Koika, V., Petrou, C., Cordopatis, P., Sessa, W. C., et al. (2007). The phosphodiesterase 5 inhibitor sildenafil stimulates angiogenesis through a protein kinase G/MAPK pathway. Journal of Cellular Physiology, 211, 197–204.

    Article  CAS  PubMed  Google Scholar 

  79. Soderling, S. H., Bayuga, S. J., & Beavo, J. A. (1998). Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase. Proceedings of the National Academy of Sciences of the United States of America, 95, 8991–8996.

    Article  CAS  PubMed  Google Scholar 

  80. Salloum, F. N., Abbate, A., Das, A., Houser, J. E., Mudrick, C. A., Qureshi, I. Z., et al. (2008). Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice. American Journal of Physiology. Heart and Circulatory Physiology, 294, H1398–1406.

    Article  CAS  PubMed  Google Scholar 

  81. Rochais, F., Abi-Gerges, A., Horner, K., Lefebvre, F., Cooper, D. M., Conti, M., et al. (2006). A specific pattern of phosphodiesterases controls the cAMP signals generated by different Gs-coupled receptors in adult rat ventricular myocytes. Circulation Research, 98, 1081–1088.

    Article  CAS  PubMed  Google Scholar 

  82. Verde, I., Vandecasteele, G., Lezoualc’h, F., & Fischmeister, R. (1999). Characterization of the cyclic nucleotide phosphodiesterase subtypes involved in the regulation of the L-type Ca2+ current in rat ventricular myocytes. British Journal of Pharmacology, 127, 65–74.

    Article  CAS  PubMed  Google Scholar 

  83. Vandecasteele, G., Verde, I., Rucker-Martin, C., Donzeau-Gouge, P., & Fischmeister, R. (2001). Cyclic GMP regulation of the L-type Ca(2+) channel current in human atrial myocytes. Journal de Physiologie, 533, 329–340.

    Article  CAS  Google Scholar 

  84. Malecot, C. O., Bers, D. M., & Katzung, B. G. (1986). Biphasic contractions induced by milrinone at low temperature in ferret ventricular muscle: Role of the sarcoplasmic reticulum and transmembrane calcium influx. Circulation Research, 59, 151–162.

    CAS  PubMed  Google Scholar 

  85. Yano, M., Kohno, M., Ohkusa, T., Mochizuki, M., Yamada, J., Hisaoka, T., et al. (2000). Effect of milrinone on left ventricular relaxation and Ca(2+) uptake function of cardiac sarcoplasmic reticulum. American Journal of Physiology. Heart and Circulatory Physiology, 279, H1898–1905.

    CAS  PubMed  Google Scholar 

  86. Baillie, G. S., Sood, A., McPhee, I., Gall, I., Perry, S. J., Lefkowitz, R. J., et al. (2003). beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proceedings of the National Academy of Sciences of the United States of America, 100, 940–945.

    Article  CAS  PubMed  Google Scholar 

  87. Das, A., Ockaili, R., Salloum, F., & Kukreja, R. C. (2004). Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits. American Journal of Physiology. Heart and Circulatory Physiology, 286, H1455–1460.

    Article  CAS  PubMed  Google Scholar 

  88. Senzaki, H., Smith, C. J., Juang, G. J., Isoda, T., Mayer, S. P., Ohler, A., et al. (2001). Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. The FASEB Journal, 15, 1718–1726.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chen Yan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Miller, C.L., Yan, C. Targeting Cyclic Nucleotide Phosphodiesterase in the Heart: Therapeutic Implications. J. of Cardiovasc. Trans. Res. 3, 507–515 (2010). https://doi.org/10.1007/s12265-010-9203-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-010-9203-9

Keywords

Navigation