Advertisement

Current Heart Failure Reports

, Volume 9, Issue 3, pp 192–199 | Cite as

Cardiac Role of Cyclic-GMP Hydrolyzing Phosphodiesterase Type 5: From Experimental Models to Clinical Trials

  • David A. KassEmail author
Investigative Therapies (J.-L. Balligand, Section editor)

Abstract

Cyclic guanosine monophosphate (cGMP) and its primary signaling kinase, protein kinase G, play an important role in counterbalancing stress remodeling in the heart. Growing evidence supports a positive impact on a variety of cardiac disease conditions from the suppression of cGMP hydrolysis. The latter is regulated by members of the phosphodiesterase (PDE) superfamily, of which cGMP-selective PDE5 has been best studied. Inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischemic injury, and cardiotoxicity. Clinical trials have begun exploring their potential to benefit dilated cardiomyopathy and heart failure with a preserved ejection fraction. This review discusses recent developments in the field, highlighting basic science and clinical studies.

Keywords

Cyclic guanosine monophosphate Protein kinase G Cyclic GMP-dependent protein kinase Phosphodiesterase PDE5 PDE2 PDE1 Sildenafil Tadalafil Heart failure Hypertrophy Ventricular function Remodeling Fibrosis Transforming growth factor beta Cyclic AMP Signal transduction RGS2 TRPC channel Ischemia Preconditioning Mitochondria Human Genetic models 

Notes

Funding

Dr. David Kass has received grants from the National Institutes of Health.

Disclosures

None.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    • Tsai EJ, Kass DA. Cyclic gmp signaling in cardiovascular pathophysiology and therapeutics. Pharmacol. Ther. 2009;122:216–38. This is a useful and fairly recent review focusing on cardiovascular role of the cGMP-PKG signaling pathway. Google Scholar
  2. 2.
    •• Francis SH, Busch JL, Corbin JD, Sibley D. Cgmp-dependent protein kinases and cgmp phosphodiesterases in nitric oxide and cgmp action. Pharmacol Rev. 2010;62:525-63. This is an excellent review focusing on the molecular biology and biochemistry of the cGMP phosphodiesterases, and their signaling via PKG. Google Scholar
  3. 3.
    Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006;58:488–520.PubMedCrossRefGoogle Scholar
  4. 4.
    • Zhang M, Kass DA. Phosphodiesterases and cardiac cgmp: Evolving roles and controversies. Trends Pharmacol Sci. 2011;32:360-365. This article discusses in particular the controversies surrounding which PDEs are most important to cardiac cGMP modulation in the heart, and the potential for this pathway to provide a novel therapeutic avenue. Google Scholar
  5. 5.
    Castro LR, Verde I, Cooper DM, Fischmeister R. Cyclic guanosine monophosphate compartmentation in rat cardiac myocytes. Circulation. 2006;113:2221–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Mongillo M, Tocchetti CG, Terrin A, Lissandron V, Cheung YF, Dostmann WR, Pozzan T, Kass DA, Paolocci N, Houslay MD, Zaccolo M. Compartmentalized phosphodiesterase-2 activity blunts beta-adrenergic cardiac inotropy via an no/cgmp-dependent pathway. Circ Res. 2006;98:226–34.PubMedCrossRefGoogle Scholar
  7. 7.
    Stangherlin A, Gesellchen F, Zoccarato A, Terrin A, Fields LA, Berrera M, Surdo NC, Craig MA, Smith G, Hamilton G, Zaccolo M. Cgmp signals modulate camp levels in a compartment-specific manner to regulate catecholamine-dependent signaling in cardiac myocytes. Circ Res. 2011;108:929–39.PubMedCrossRefGoogle Scholar
  8. 8.
    Wallis RM, Corbin JD, Francis SH, Ellis P. 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. Am J Cardiol. 1999;83:3C–12C.PubMedCrossRefGoogle Scholar
  9. 9.
    Senzaki H, Smith CJ, Juang GJ, Isoda T, Mayer SP, Ohler A, Paolocci N, Tomaselli GF, Hare JM, Kass DA. Cardiac phosphodiesterase 5 (cgmp-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. FASEB J. 2001;15:1718–26.PubMedCrossRefGoogle Scholar
  10. 10.
    Ockaili R, Salloum F, Hawkins J, Kukreja RC. Sildenafil (viagra) induces powerful cardioprotective effect via opening of mitochondrial k(atp) channels in rabbits. Am J Physiol Heart Circ Physiol. 2002;283:H1263–9.PubMedGoogle Scholar
  11. 11.
    Corbin J, Rannels S, Neal D, Chang P, Grimes K, Beasley A, Francis S. Sildenafil citrate does not affect cardiac contractility in human or dog heart. Curr Med Res Opin. 2003;19:747–52.PubMedCrossRefGoogle Scholar
  12. 12.
    Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–57.PubMedCrossRefGoogle Scholar
  13. 13.
    Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic gmp phosphodiesterase 5a prevents and reverses cardiac hypertrophy. Nat Med. 2005;11:214–22.PubMedCrossRefGoogle Scholar
  14. 14.
    Das A, Xi L, Kukreja RC. Protein kinase g dependent cardioprotective mechanism of phosphodiesterase-5 inhibition involves phosphorylation of erk and gsk3beta. J Biol Chem. 2008;283:29572–85.PubMedCrossRefGoogle Scholar
  15. 15.
    Das A, Smolenski A, Lohmann SM, Kukreja RC. Cyclic gmp-dependent protein kinase ialpha attenuates necrosis and apoptosis following ischemia/reoxygenation in adult cardiomyocyte. J Biol Chem. 2006;281:38644–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Salloum FN, Abbate A, Das A, Houser JE, Mudrick CA, Qureshi I, Hoke NN, Roy SK, Brown WR, Prabhakar S, Kukreja RC. Sildenafil (viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice. Am J Physiol Heart Circ Physiol. 2008;294:H1398–406.PubMedCrossRefGoogle Scholar
  17. 17.
    Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation. 2005;111:1601–10.PubMedCrossRefGoogle Scholar
  18. 18.
    Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccolo M, Dostmann WR, Smith CJ, Kass DA. Cgmp catabolism by phosphodiesterase 5a regulates cardiac adrenergic stimulation by nos3-dependent mechanism. Circ Res. 2005;96:100–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Borlaug BA, Melenovsky V, Marhin T, Fitzgerald P, Kass DA. Sildenafil inhibits beta-adrenergic-stimulated cardiac contractility in humans. Circulation. 2005;112:2642–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Dai W, Kloner RA. Is inhibition of phosphodiesterase type 5 by sildenafil a promising therapy for volume-overload heart failure? Circulation. 2012;125:1341–3.PubMedCrossRefGoogle Scholar
  21. 21.
    Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St AC, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JR, Michelakis ED. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation. 2007;116:238–48.PubMedCrossRefGoogle Scholar
  22. 22.
    Lu Z, Xu X, Hu X, Lee S, Traverse JH, Zhu G, Fassett J, Tao Y, Zhang P, dos Remedios C, Pritzker M, Hall JL, Garry DJ, Chen Y. Oxidative stress regulates left ventricular pde5 expression in the failing heart. Circulation. 2010;121:1474–83.PubMedCrossRefGoogle Scholar
  23. 23.
    Pokreisz P, Vandenwijngaert S, Bito V, Van den BA, Lenaerts I, Busch C, Marsboom G, Gheysens O, Vermeersch P, Biesmans L, Liu X, Gillijns H, Pellens M, Van LA, Buys E, Schoonjans L, Vanhaecke J, Verbeken E, Sipido K, Herijgers P, Bloch KD, Janssens SP. Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice. Circulation. 2009;119:408–16.PubMedCrossRefGoogle Scholar
  24. 24.
    Shan X, Quaile MP, Monk JK, French B, Cappola TP, Margulies KB. Differential expression of pde5 in failing and nonfailing human myocardium. Circ Heart Fail. 2012;5:79–86.PubMedCrossRefGoogle Scholar
  25. 25.
    Johnson WB, Katugampola S, Able S, Napier C, Harding SE. Profiling of camp and cgmp phosphodiesterases in isolated ventricular cardiomyocytes from human hearts: comparison with rat and guinea pig. Life Sci. 2012;90:328–36.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhang M, Koitabashi N, Nagayama T, Rambaran R, Feng N, Takimoto E, Koenke T, O'Rourke B, Champion HC, Crow MT, Kass DA. Expression, activity, and pro-hypertrophic effects of pde5a in cardiac myocytes. Cell Signal. 2008;20:2231–6.PubMedCrossRefGoogle Scholar
  27. 27.
    • Castro LR, Schittl J, Fischmeister R. Feedback control through cgmp-dependent protein kinase contributes to differential regulation and compartmentation of cgmp in rat cardiac myocytes. Circ Res. 2010;107:1232-40. This is an important new study identifying selective feedback and feedforward targeting of different cGMP synthetic pathways by PDEs. Google Scholar
  28. 28.
    Rybalkin SD, Rybalkina IG, Shimizu-Albergine M, Tang XB, Beavo JA. Pde5 is converted to an activated state upon cgmp binding to the gaf a domain. EMBO J. 2003;22:469–78.PubMedCrossRefGoogle Scholar
  29. 29.
    Corbin JD, Turko IV, Beasley A, Francis SH. Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cgmp-binding activities. Eur J Biochem. 2000;267:2760–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Takimoto E, Belardi D, Tocchetti CG, Vahebi S, Cormaci G, Ketner EA, Moens AL, Champion HC, Kass DA. Compartmentalization of cardiac beta-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation. 2007;115:2159–67.PubMedCrossRefGoogle Scholar
  31. 31.
    Lee DI, Vahebi S, Tocchetti CG, Barouch LA, Solaro RJ, Takimoto E, Kass DA. Pde5a suppression of acute beta-adrenergic activation requires modulation of myocyte beta-3 signaling coupled to pkg-mediated troponin i phosphorylation. Basic Res Cardiol. 2010;105:337–47.PubMedCrossRefGoogle Scholar
  32. 32.
    Bishu K, Hamdani N, Mohammed SF, Kruger M, Ohtani T, Ogut O, Brozovich FV, Burnett Jr JC, Linke WA, Redfield MM. Sildenafil and b-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo. Circulation. 2011;124:2882–91.PubMedCrossRefGoogle Scholar
  33. 33.
    •• Kukreja RC, Salloum FN, Das A. Cyclic guanosine monophosphate signaling and phosphodiesterase-5 inhibitors in cardioprotection. J Am Coll Cardiol. 2012;59:1921-1927. This is an excellent recent review from the group that provided the majority of data regarding the influence of PDE5 regulation and ischemic injury and cardioprotection. Google Scholar
  34. 34.
    Koka S, Das A, Zhu SG, Durrant D, Xi L, Kukreja RC. Long-acting phosphodiesterase-5 inhibitor tadalafil attenuates doxorubicin-induced cardiomyopathy without interfering with chemotherapeutic effect. J Pharmacol Exp Ther. 2010;334:1023–30.PubMedCrossRefGoogle Scholar
  35. 35.
    Salloum F, Yin C, Xi L, Kukreja RC. Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart. Circ Res. 2003;92:595–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Milano G, Bianciardi P, Rochemont V, Vassalli G, Segesser LK, Corno AF, Guazzi M, Samaja M. Phosphodiesterase-5 inhibition mimics intermittent reoxygenation and improves cardioprotection in the hypoxic myocardium. PloS one. 2011;6:e27910.PubMedCrossRefGoogle Scholar
  37. 37.
    Hoke NN, Salloum FN, Kass DA, Das A, Kukreja RC. Preconditioning by phosphodiesterase-5 inhibition improves therapeutic efficacy of adipose-derived stem cells following myocardial infarction in mice. Stem Cells. 2012;30:326–35.PubMedCrossRefGoogle Scholar
  38. 38.
    Fischer KM, Cottage CT, Konstandin MH, Volkers M, Khan M, Sussman MA. Pim-1 kinase inhibits pathological injury by promoting cardioprotective signaling. J Mol Cell Cardiol. 2011;51:554–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Nishida M, Watanabe K, Sato Y, Nakaya M, Kitajima N, Ide T, Inoue R, Kurose H. Phosphorylation of trpc6 channels at thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition. J Biol Chem. 2010;285:13244–53.PubMedCrossRefGoogle Scholar
  40. 40.
    •• Takimoto E, Koitabashi N, Hsu S, Ketner EA, Zhang M, Nagayama T, Bedja D, Gabrielson KL, Blanton R, Siderovski DP, Mendelsohn ME, Kass DA. Regulator of g protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of pde5 inhibition in mice. J Clin Invest. 2009;119:408-20. This was an important study that first identified a major requisite signaling pathway to PDE5-inhibitor suppression of cardiac maladaption to pressure-overload. PKG interaction with and activation of RGS2 is shown to be required for initial adaptions to this stress. Google Scholar
  41. 41.
    • Kinoshita H, Kuwahara K, Nishida M, Jian Z, Rong X, Kiyonaka S, Kuwabara Y, Kurose H, Inoue R, Mori Y, Li Y, Nakagawa Y, Usami S, Fujiwara M, Yamada Y, Minami T, Ueshima K, Nakao K. Inhibition of trpc6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-a signaling in the heart. Circ Res. 2010;106:1849-1860. This is an important study that revealed the importance of NP-stimulated PKG activation in suppression hypertrophy via TRPC6 modification. Google Scholar
  42. 42.
    • Koitabashi N, Aiba T, Hesketh GG, Rowell J, Zhang M, Takimoto E, Tomaselli GF, Kass DA. Cyclic gmp/pkg-dependent inhibition of trpc6 channel activity and expression negatively regulates cardiomyocyte nfat activation novel mechanism of cardiac stress modulation by pde5 inhibition. J Mol Cell Cardiol. 2010;48:713-724. This is a similar report to reference 32, appeared earlier, and first established the sites of PKG-modification in TRPC6 and its role in the cellular-antihypertrophic effects of sildenafil. Google Scholar
  43. 43.
    Chau VQ, Salloum FN, Hoke NN, Abbate A, Kukreja RC. Mitigation of the progression of heart failure with sildenafil involves inhibition of rhoa/rho-kinase pathway. American journal of physiology. Heart and circulatory physiology. 2011;300:H2272-79Google Scholar
  44. 44.
    Kim KH, Kim YJ, Ohn JH, Yang J, Lee SE, Lee SW, Kim HK, Seo JW, Sohn DW. Long-term effects of sildenafil in a rat model of chronic mitral regurgitation: benefits of ventricular remodeling and exercise capacity. Circulation. 2012;125:1390–401.PubMedCrossRefGoogle Scholar
  45. 45.
    Lukowski R, Rybalkin SD, Loga F, Leiss V, Beavo JA, Hofmann F. Cardiac hypertrophy is not amplified by deletion of cgmp-dependent protein kinase i in cardiomyocytes. Proc Natl Acad Sci USA. 2010;107:5646–51.PubMedCrossRefGoogle Scholar
  46. 46.
    •• Zhang M, Takimoto E, Hsu S, Lee DI, Nagayama T, Danner T, Koitabashi N, Barth AS, Bedja D, Gabrielson KL, Wang Y, Kass DA. Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5. J Am Coll Cardiol. 2010;56:2021-2030. This study revealed the critical role of myocyte PKG activation modulated by PDE5 activity in cardiac stress adaptations or maladaptations, and uses a novel conditional genetic model to modify PDE5 activation in myocytes only. Google Scholar
  47. 47.
    Frantz S, Klaiber M, Baba HA, Oberwinkler H, Volker K, Gassner B, Bayer B, Abesser M, Schuh K, Feil R, Hofmann F, Kuhn M. Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic gmp-dependent protein kinase i. Eur Heart J. 2012 (ebup ahead of print; doi:10.1093/eurheart/ehr-445).
  48. 48.
    Lukowski R, Rybalkin SD, Loga F, Leiss V, Beavo JA, Hofmann F. Cardiac hypertrophy is not amplified by deletion of cgmp-dependent protein kinase i in cardiomyocytes. Proc Natl Acad Sci U S A. 2010;107:5646–51.PubMedCrossRefGoogle Scholar
  49. 49.
    Li L, Haider HK, Wang L, Lu G, Ashraf M. Adenoviral short hairpin rna therapy targeting pde5a relieves cardiac remodeling and dysfunction following myocardial infarction. Am J Physiol Heart Circ Physiol. 2012;302:H2112–21.PubMedCrossRefGoogle Scholar
  50. 50.
    • Shan X, Quaile MP, Monk JK, French B, Cappola TP, Margulies KB. Differential expression of pde5 in failing and nonfailing human myocardium. Circ Heart Fail. 2012;5:79-86. This is a recent clinical study that supports upregulation of PDE5 expression in various forms of human cardiac failure. Google Scholar
  51. 51.
    Pokreisz P, Vandenwijngaert S, Bito V, Van den BA, Lenaerts I, Busch C, Marsboom G, Gheysens O, Vermeersch P, Biesmans L, Liu X, Gillijns H, Pellens M, Van Lommel A, Buys E, Schoonjans L, Vanhaecke J, Verbeken E, Sipido K, Herijgers P, Bloch KD, Janssens SP. Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice. Circulation. 2009;119:408–16.PubMedCrossRefGoogle Scholar
  52. 52.
    Lewis GD, Lachmann J, Camuso J, Lepore JJ, Shin J, Martinovic ME, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. Circulation. 2007;115:59–66.PubMedCrossRefGoogle Scholar
  53. 53.
    Lewis GD, Semigran MJ. Type 5 phosphodiesterase inhibition in heart failure and pulmonary hypertension. Curr Heart Fail Rep. 2004;1:183–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol. 2007;50:2136–44.PubMedCrossRefGoogle Scholar
  55. 55.
    Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol. 2004;44:2339–48.PubMedCrossRefGoogle Scholar
  56. 56.
    •• Guazzi M, Vincenzi M, Arena R, Guazzi MD. Pde5-inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: Results of a 1-year prospective, randomized, placebo-controlled study. Circ: Heart Fail. 2011;4:8-17. This recent study provided the first clinical evidence for sustained improvement in LV function in patients with heart failure treated with chronic sildenafil. Google Scholar
  57. 57.
    Guazzi M, Vicenzi M, Arena R. Phosphodiesterase 5 inhibition with sildenafil reverses exercise oscillatory breathing in chronic heart failure: a long-term cardiopulmonary exercise testing placebo-controlled study. Eur J Heart Fail. 2012;14:82–90.PubMedCrossRefGoogle Scholar
  58. 58.
    Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pde5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: Results of a 1-year, prospective, randomized, placebo-controlled study. Circ Heart Fail. 2011;4:8–17.PubMedCrossRefGoogle Scholar
  59. 59.
    Giannetta E, Isidori AM, Galea N, Carbone I, Mandosi E, Vizza CD, Naro F, Morano S, Fedele F, Lenzi A. Chronic inhibition of cyclic gmp phosphodiesterase 5a improves diabetic cardiomyopathy: A randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation. 2012 (epub ahead of print) 10.1161/circulationaha.111.063412.
  60. 60.
    Koka S, Xi L, Kukreja RC. Chronic treatment with long acting phosphodiesterase-5 inhibitor tadalafil alters proteomic changes associated with cytoskeletal rearrangement and redox regulation in type 2 diabetic hearts. Basic Res Cardiol. 2012;107:249.PubMedCrossRefGoogle Scholar
  61. 61.
    Lindman BR, Zajarias A, Madrazo JA, Shah J, Gage BF, Novak E, Johnson SN, Chakinala MM, Hohn TA, Saghir M, Mann DL. Effects of phosphodiesterase type 5 inhibition on systemic and pulmonary hemodynamics and ventricular function in patients with severe symptomatic aortic stenosis. Circulation. 2012;125:2353–62.PubMedCrossRefGoogle Scholar
  62. 62.
    Goldberg DJ, French B, Szwast AL, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G, Paridon SM, Rychik J. Impact of sildenafil on echocardiographic indices of myocardial performance after the fontan operation. Pediatric cardiology. 2012.Google Scholar
  63. 63.
    Miller CL, Oikawa M, Cai Y, Wojtovich AP, Nagel DJ, Xu X, Xu H, Florio V, Rybalkin SD, Beavo JA, Chen YF, Li JD, Blaxall BC, Abe J, Yan C. Role of ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy. Circ Res. 2009;105:956–64.PubMedCrossRefGoogle Scholar
  64. 64.
    Miller CL, Cai Y, Oikawa M, Thomas T, Dostmann WR, Zaccolo M, Fujiwara K, Yan C. Cyclic nucleotide phosphodiesterase 1a: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart. Basic Res Cardiol. 2011;106:1023–39.PubMedCrossRefGoogle Scholar
  65. 65.
    •• Chan S, Yan C. Pde1 isozymes, key regulators of pathological vascular remodeling. Curr Opin Pharmacol. 2011;11:720-724. This is a nice review of recent work on PDE1 and its role in blood vessels. Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Cardiology, Department of MedicineThe Johns Hopkins Medical InstitutionsBaltimoreUSA

Personalised recommendations