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Heart Failure pp 249-269 | Cite as

Cardiac Phosphodiesterases and Their Modulation for Treating Heart Disease

  • Grace E. Kim
  • David A. KassEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 243)

Abstract

An important hallmark of cardiac failure is abnormal second messenger signaling due to impaired synthesis and catabolism of cyclic adenosine 3′,5′- monophosphate (cAMP) and cyclic guanosine 3′,5′- monophosphate (cGMP). Their dysregulation, altered intracellular targeting, and blunted responsiveness to stimulating pathways all contribute to pathological remodeling, muscle dysfunction, reduced cell survival and metabolism, and other abnormalities. Therapeutic enhancement of either cyclic nucleotides can be achieved by stimulating their synthesis and/or by suppressing members of the family of cyclic nucleotide phosphodiesterases (PDEs). The heart expresses seven of the eleven major PDE subtypes – PDE1, 2, 3, 4, 5, 8, and 9. Their differential control over cAMP and cGMP signaling in various cell types, including cardiomyocytes, provides intriguing therapeutic opportunities to counter heart disease. This review examines the roles of these PDEs in the failing and hypertrophied heart and summarizes experimental and clinical data that have explored the utility of targeted PDE inhibition.

Keywords

Cyclic nucleotides Heart failure Myocardium Phosphodiesterases Protein kinase A Protein kinase G 

References

  1. Adamo CM et al (2010) Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 107:19079–19083PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ahmad F et al (2015) Regulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) activity by phosphodiesterase 3A (PDE3A) in human myocardium: phosphorylation-dependent interaction of PDE3A1 with SERCA2. J Biol Chem 290:6763–6776PubMedPubMedCentralCrossRefGoogle Scholar
  3. Albert CL, Sleeper M, Sweeney HL (2012) Abstract 9504: phosphodiesterase modulation of cardiomyopathy in Murine and Canine models of muscular dystrophy treated with sildenafil and tadalafil. Circulation 126:A9504Google Scholar
  4. Andersen RO et al (2012) Sgt1 acts via an LKB1/AMPK pathway to establish cortical polarity in larval neuroblasts. Dev Biol 363:258–265PubMedPubMedCentralCrossRefGoogle Scholar
  5. Beca S et al (2013) Phosphodiesterase type 3A regulates basal myocardial contractility through interacting with sarcoplasmic reticulum calcium ATPase type 2a signaling complexes in mouse heart. Circ Res 112:289–297PubMedCrossRefGoogle Scholar
  6. Behling A et al (2008) Effects of 5′-phosphodiesterase four-week long inhibition with sildenafil in patients with chronic heart failure: a double-blind, placebo-controlled clinical trial. J Card Fail 14:189–197PubMedCrossRefGoogle Scholar
  7. Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58:488–520PubMedCrossRefGoogle Scholar
  8. Bishu K et al (2011) Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo. Circulation 124:2882–2891PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bobin P et al (2016) Calmodulin kinase II inhibition limits the pro-arrhythmic Ca2+ waves induced by cAMP-phosphodiesterase inhibitors. Cardiovasc Res 110:151–161PubMedCrossRefGoogle Scholar
  10. Brenman JE et al (1995) Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy. Cell 82:743–752PubMedCrossRefGoogle Scholar
  11. Chen W et al (2016) Endothelial actions of ANP enhance myocardial inflammatory infiltration in the early phase after acute infarction. Circ Res 119:237–248PubMedCrossRefGoogle Scholar
  12. Chung YW et al (2015) Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury. Proc Natl Acad Sci U S A 112:E2253–E2262PubMedPubMedCentralCrossRefGoogle Scholar
  13. Corbin JD et al (2000) Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur J Biochem 267:2760–2767PubMedCrossRefGoogle Scholar
  14. Cuffe MS et al (2002) Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 287:1541–1547PubMedCrossRefGoogle Scholar
  15. Cygnar KD, Zhao H (2009) Phosphodiesterase 1C is dispensable for rapid response termination of olfactory sensory neurons. Nat Neurosci 12:454–462PubMedPubMedCentralCrossRefGoogle Scholar
  16. Das A, Xi L, Kukreja RC (2008) Protein kinase G-dependent cardioprotective mechanism of phosphodiesterase-5 inhibition involves phosphorylation of ERK and GSK3beta. J Biol Chem 283:29572–29585PubMedPubMedCentralCrossRefGoogle Scholar
  17. Degen CV et al (2015) The emperor’s new clothes: PDE5 and the heart. PLoS One 10, e0118664PubMedPubMedCentralCrossRefGoogle Scholar
  18. DiBianco R et al (1989) A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med 320:677–683PubMedCrossRefGoogle Scholar
  19. Ding B et al (2005) Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: implication in heart failure. Circulation 111:2469–2476PubMedPubMedCentralCrossRefGoogle Scholar
  20. Duinen MV et al (2015) Treatment of cognitive impairment in schizophrenia: potential value of phosphodiesterase inhibitors in prefrontal dysfunction. Curr Pharm Des 21:3813–3828PubMedCrossRefGoogle Scholar
  21. Esseltine JL, Scott JD (2013) AKAP signaling complexes: pointing towards the next generation of therapeutic targets? Trends Pharmacol Sci 34:648–655PubMedCrossRefGoogle Scholar
  22. Fields LA, Koschinski A, Zaccolo M (2016) Sustained exposure to catecholamines affects cAMP/PKA compartmentalised signalling in adult rat ventricular myocytes. Cell Signal 28:725–732PubMedPubMedCentralCrossRefGoogle Scholar
  23. Fischmeister R et al (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of cyclic nucleotide phosphodiesterases. Circ Res 99:816–828PubMedCrossRefGoogle Scholar
  24. Fisher DA et al (1998) Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase. J Biol Chem 273:15559–15564PubMedCrossRefGoogle Scholar
  25. Francis SH et al (2002) Phosphorylation of isolated human phosphodiesterase-5 regulatory domain induces an apparent conformational change and increases cGMP binding affinity. J Biol Chem 277:47581–47587PubMedCrossRefGoogle Scholar
  26. Francis SH, Blount MA, Corbin JD (2011) Mammalian cyclic nucleotide phosphodiesterases: Molecular mechanisms and physiological functions. Physiol Rev 91:651–690PubMedCrossRefGoogle Scholar
  27. Ghofrani HA et al (2004) Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol 44:1488–1496PubMedGoogle Scholar
  28. Giannetta E et al (2012) Chronic inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation 125:2323–2333PubMedCrossRefGoogle Scholar
  29. Gloerich M, Bos JL (2010) Epac: defining a new mechanism for cAMP action. Annu Rev Pharmacol Toxicol 50:355–375PubMedCrossRefGoogle Scholar
  30. Guazzi M et al (2011) Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation 124:164–174PubMedCrossRefGoogle Scholar
  31. Hammers DW et al (2016) Tadalafil treatment delays the onset of cardiomyopathy in dystrophin-deficient hearts. J Am Heart Assoc 5, e003911PubMedPubMedCentralCrossRefGoogle Scholar
  32. Haynes MP et al (2000) Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ Res 87:677–682PubMedCrossRefGoogle Scholar
  33. Heckman PR, Wouters C, Prickaerts J (2015) Phosphodiesterase inhibitors as a target for cognition enhancement in aging and Alzheimer’s disease: a translational overview. Curr Pharm Des 21:317–331PubMedCrossRefGoogle Scholar
  34. Ho JE et al (2014) Effect of phosphodiesterase inhibition on insulin resistance in obese individuals. J Am Heart Assoc 3, e001001PubMedPubMedCentralCrossRefGoogle Scholar
  35. Hoendermis ES et al (2015) Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J 36:2565–2573PubMedCrossRefGoogle Scholar
  36. Kentish JC et al (2001) Phosphorylation of troponin I by protein kinase A accelerates relaxation and crossbridge cycle kinetics in mouse ventricular muscle. Circ Res 88:1059–1065PubMedCrossRefGoogle Scholar
  37. Kim KH et al (2015) PDE 5 inhibition with udenafil improves left ventricular systolic/diastolic functions and exercise capacity in patients with chronic heart failure with reduced ejection fraction; A 12-week, randomized, double-blind, placebo-controlled trial. Am Heart J 169(813–822), e3Google Scholar
  38. Kinoshita H et al (2010) Inhibition of TRPC6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart. Circ Res 106:1849–1860PubMedCrossRefGoogle Scholar
  39. Knight WE et al (2014) Abstract 25: the role of cAMP-phosphodiesterase 1C signaling in pathological cardiac remodeling and dysfunction. Circ Res 115:A25Google Scholar
  40. Kobayashi K et al (2007) Relation of spasms and myoclonus to suppression-burst on EEG in epileptic encephalopathy in early infancy. Neuropediatrics 38:244–250PubMedCrossRefGoogle Scholar
  41. Koitabashi N et al (2010) 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 48:713–724PubMedCrossRefGoogle Scholar
  42. Lee DI et al (2015) Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature 519:472–476PubMedPubMedCentralCrossRefGoogle Scholar
  43. Leroy J et al (2008) Spatiotemporal dynamics of beta-adrenergic cAMP signals and L-type Ca2+ channel regulation in adult rat ventricular myocytes: role of phosphodiesterases. Circ Res 102:1091–1100PubMedCrossRefGoogle Scholar
  44. Leung SW et al (2007) Non-genomic vascular actions of female sex hormones: physiological implications and signalling pathways. Clin Exp Pharmacol Physiol 34:822–826PubMedCrossRefGoogle Scholar
  45. Leung DG et al (2014) Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy. Ann Neurol 76:541–549PubMedPubMedCentralCrossRefGoogle Scholar
  46. Lewis GD et al (2007) Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 116:1555–1562PubMedCrossRefGoogle Scholar
  47. Loufrani L, Levy BI, Henrion D (2002) Defect in microvascular adaptation to chronic changes in blood flow in mice lacking the gene encoding for dystrophin. Circ Res 91:1183–1189PubMedCrossRefGoogle Scholar
  48. Loughney K et al (1996) Isolation and characterization of cDNAs corresponding to two human calcium, calmodulin-regulated, 3′,5′-cyclic nucleotide phosphodiesterases. J Biol Chem 271:796–806PubMedCrossRefGoogle Scholar
  49. Lu Z et al (2010) Oxidative stress regulates left ventricular PDE5 expression in the failing heart. Circulation 121:1474–83PubMedPubMedCentralCrossRefGoogle Scholar
  50. Lukowski R et al (2010) Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes. Proc Natl Acad Sci U S A 107:5646–5651PubMedPubMedCentralCrossRefGoogle Scholar
  51. MacLennan DH, Kranias EG (2003) Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4:566–577PubMedCrossRefGoogle Scholar
  52. Martins TJ, Mumby MC, Beavo JA (1982) Purification and characterization of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase from bovine tissues. J Biol Chem 257:1973–1979PubMedGoogle Scholar
  53. Maurice DH et al (2014) Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 13:290–314PubMedPubMedCentralCrossRefGoogle Scholar
  54. Meacci E et al (1992) Molecular cloning and expression of human myocardial cGMP-inhibited cAMP phosphodiesterase. Proc Natl Acad Sci U S A 89:3721–3725PubMedPubMedCentralCrossRefGoogle Scholar
  55. Mehel H et al (2013) Phosphodiesterase-2 is up-regulated in human failing hearts and blunts beta-adrenergic responses in cardiomyocytes. J Am Coll Cardiol 62:1596–1606PubMedCrossRefGoogle Scholar
  56. Metra M et al (2009) Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials. Eur Heart J 30:3015–3026PubMedPubMedCentralCrossRefGoogle Scholar
  57. Mika D et al (2013) Differential regulation of cardiac excitation-contraction coupling by cAMP phosphodiesterase subtypes. Cardiovasc Res 100:336–346PubMedPubMedCentralCrossRefGoogle Scholar
  58. Miller CL et al (2009) Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy. Circ Res 105:956–964PubMedPubMedCentralCrossRefGoogle Scholar
  59. Miller CL et al (2011) Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart. Basic Res Cardiol 106:1023–1039PubMedPubMedCentralCrossRefGoogle Scholar
  60. Mongillo M et al (2006) Compartmentalized phosphodiesterase-2 activity blunts beta-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway. Circ Res 98:226–234PubMedCrossRefGoogle Scholar
  61. Movsesian M, Wever-Pinzon O, Vandeput F (2011) PDE3 inhibition in dilated cardiomyopathy. Curr Opin Pharmacol 11:707–713PubMedPubMedCentralCrossRefGoogle Scholar
  62. Murphy RM et al (2011) Exercise oscillatory ventilation in systolic heart failure: an indicator of impaired hemodynamic response to exercise. Circulation 124:1442–1451PubMedPubMedCentralCrossRefGoogle Scholar
  63. Nagayama T et al (2007) Control of in vivo left ventricular [correction] contraction/relaxation kinetics by myosin binding protein C: protein kinase A phosphorylation dependent and independent regulation. Circulation 116:2399–2408PubMedCrossRefGoogle Scholar
  64. Nagayama T et al (2008) Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil. J Pharmacol Exp Ther 326:380–387PubMedCrossRefGoogle Scholar
  65. Nagayama T et al (2009) Pressure-overload magnitude-dependence of the anti-hypertrophic efficacy of PDE5A inhibition. J Mol Cell Cardiol 46:560–567PubMedCrossRefGoogle Scholar
  66. Nagendran J 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 116:238–248PubMedCrossRefGoogle Scholar
  67. Nakano SJ et al (2016) Cardiac adenylyl cyclase and phosphodiesterase expression profiles vary by age, disease, and chronic phosphodiesterase inhibitor treatment. J Card FailGoogle Scholar
  68. Nelson MD et al (2014) PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology 82:2085–2091PubMedPubMedCentralCrossRefGoogle Scholar
  69. Nishida M et al (2010) Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition. J Biol Chem 285:13244–13253PubMedPubMedCentralCrossRefGoogle Scholar
  70. Nygren PJ, Scott JD (2015) Therapeutic strategies for anchored kinases and phosphatases: exploiting short linear motifs and intrinsic disorder. Front Pharmacol 6:158PubMedPubMedCentralCrossRefGoogle Scholar
  71. Oikawa M et al (2013) Cyclic nucleotide phosphodiesterase 3A1 protects the heart against ischemia-reperfusion injury. J Mol Cell Cardiol 64:11–19PubMedCrossRefGoogle Scholar
  72. Packer M et al (1991) Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 325:1468–1475PubMedCrossRefGoogle Scholar
  73. Pokreisz P 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 119:408–416PubMedPubMedCentralCrossRefGoogle Scholar
  74. Ramirez CE et al (2015) Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: a Randomized. Control Trial J Clin Endocrinol Metab 100:4533–4540PubMedCrossRefGoogle Scholar
  75. Ranek MJ et al (2013) Protein kinase g positively regulates proteasome-mediated degradation of misfolded proteins. Circulation 128:365–376PubMedPubMedCentralCrossRefGoogle Scholar
  76. Redfield MM et al (2013) Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 309:1268–1277PubMedCrossRefGoogle Scholar
  77. Reiken SR et al (2003) PKA phosphorylation of the cardiac calcium release channel (ryanodine receptor) in normal and failing hearts: role of phosphatases and response to isoproterenol. J Biol Chem 278(1):444–453PubMedCrossRefGoogle Scholar
  78. Rosman GJ et al (1997) Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3′,5′-cyclic nucleotide phosphodiesterase. Gene 191:89–95PubMedCrossRefGoogle Scholar
  79. Rybalkin SD et al (2003) PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. EMBO J 22:469–478PubMedPubMedCentralCrossRefGoogle Scholar
  80. Sadhu K et al (1999) Differential expression of the cyclic GMP-stimulated phosphodiesterase PDE2A in human venous and capillary endothelial cells. J Histochem Cytochem 47:895–906PubMedCrossRefGoogle Scholar
  81. Sasaki H et al (2014) PDE5 inhibitor efficacy is estrogen dependent in female heart disease. J Clin Invest 124:2464–2471PubMedPubMedCentralCrossRefGoogle Scholar
  82. Sawada N et al (2001) cGMP-dependent protein kinase phosphorylates and inactivates RhoA. Biochem Biophys Res Commun 280:798–805PubMedCrossRefGoogle Scholar
  83. Seo K et al (2014) Hyperactive adverse mechanical stress responses in dystrophic heart are coupled to transient receptor potential canonical 6 and blocked by cGMP-protein kinase G modulation. Circ Res 114:823–832PubMedPubMedCentralCrossRefGoogle Scholar
  84. Shah SJ et al (2016) Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation 134:73–90PubMedCrossRefGoogle Scholar
  85. Shan X et al (2012) Differential expression of PDE5 in failing and nonfailing human myocardium. Circ Heart Fail 5:79–86PubMedCrossRefGoogle Scholar
  86. Shimizu-Albergine M et al (2012) cAMP-specific phosphodiesterases 8A and 8B, essential regulators of Leydig cell steroidogenesis. Mol Pharmacol 81:556–566PubMedPubMedCentralCrossRefGoogle Scholar
  87. Smith CJ et al (1997) Development of decompensated dilated cardiomyopathy is associated with decreased gene expression and activity of the milrinone-sensitive cAMP phosphodiesterase PDE3A. Circulation 96:3116–23PubMedCrossRefGoogle Scholar
  88. Soderling SH, Bayuga SJ, Beavo JA (1998) Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J Biol Chem 273:15553–15558PubMedCrossRefGoogle Scholar
  89. Stelzer JE, Patel JR, Moss RL (2006) Protein kinase A-mediated acceleration of the stretch activation response in murine skinned myocardium is eliminated by ablation of cMyBP-C. Circ Res 99:884–890PubMedCrossRefGoogle Scholar
  90. Sun B et al (2007) Role of phosphodiesterase type 3A and 3B in regulating platelet and cardiac function using subtype-selective knockout mice. Cell Signal 19:1765–1771PubMedCrossRefGoogle Scholar
  91. Surks HK et al (1999) Regulation of myosin phosphatase by a specific interaction with cGMP- dependent protein kinase Ialpha. Science 286:1583–1587PubMedCrossRefGoogle Scholar
  92. Tadalafil and Sildenafil for Duchenne Muscular Dystrophy Clinicaltrials.gov: NCT01359670Google Scholar
  93. Takimoto E et al (2005a) cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism. Circ Res 96:100–109PubMedCrossRefGoogle Scholar
  94. Takimoto E et al (2005b) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11:214–222PubMedCrossRefGoogle Scholar
  95. Takimoto E et al (2009) Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J Clin Invest 119:408–420PubMedPubMedCentralGoogle Scholar
  96. Tokudome T et al (2008) Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. Circulation 117:2329–2339PubMedCrossRefGoogle Scholar
  97. Umar S, van der Laarse A (2010) Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart. Mol Cell Biochem 333:191–201PubMedCrossRefGoogle Scholar
  98. van Heerebeek L et al (2012) Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 126:830–839PubMedCrossRefGoogle Scholar
  99. Vandecasteele G et al (2001) Cyclic GMP regulation of the L-type Ca(2+) channel current in human atrial myocytes. J Physiol 533:329–340PubMedPubMedCentralCrossRefGoogle Scholar
  100. Vandeput F et al (2007) Cyclic nucleotide phosphodiesterase PDE1C1 in human cardiac myocytes. J Biol Chem 282:32749–32757PubMedCrossRefGoogle Scholar
  101. Vandeput F et al (2013) Selective regulation of cyclic nucleotide phosphodiesterase PDE3A isoforms. Proc Natl Acad Sci U S A 110:19778–19783PubMedPubMedCentralCrossRefGoogle Scholar
  102. Verde I et al (1999) Characterization of the cyclic nucleotide phosphodiesterase subtypes involved in the regulation of the L-type Ca2+ current in rat ventricular myocytes. Br J Pharmacol 127:65–74PubMedPubMedCentralCrossRefGoogle Scholar
  103. Vandenwijngaert S et al (2013) Increased cardiac myocyte PDE5 levels in human and murine pressure overload hypertrophy contribute to adverse LV remodeling. PLoS One 8, e58841PubMedPubMedCentralCrossRefGoogle Scholar
  104. Wang P et al (2003) Identification and characterization of a new human type 9 cGMP-specific phosphodiesterase splice variant (PDE9A5). Differential tissue distribution and subcellular localization of PDE9A variants. Gene 314:15–27PubMedCrossRefGoogle Scholar
  105. Wechsler J et al (2002) Isoforms of cyclic nucleotide phosphodiesterase PDE3A in cardiac myocytes. J Biol Chem 277:38072–38078PubMedCrossRefGoogle Scholar
  106. Weishaar RE et al (1987) Subclasses of cyclic AMP-specific phosphodiesterase in left ventricular muscle and their involvement in regulating myocardial contractility. Circ Res 61:539–547PubMedCrossRefGoogle Scholar
  107. Yamasaki R et al (2002) Protein kinase A phosphorylates titin’s cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes. Circ Res 90:1181–1188PubMedCrossRefGoogle Scholar
  108. Yan C 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. Circ Res 100:510–519PubMedPubMedCentralCrossRefGoogle Scholar
  109. Yanaka N et al (2003) cGMP-phosphodiesterase activity is up-regulated in response to pressure overload of rat ventricles. Biosci Biotechnol Biochem 67:973–979PubMedCrossRefGoogle Scholar
  110. Zaccolo M (2009) cAMP signal transduction in the heart: understanding spatial control for the development of novel therapeutic strategies. Br J Pharmacol 158:50–60PubMedPubMedCentralCrossRefGoogle Scholar
  111. Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295:1711–1715PubMedCrossRefGoogle Scholar
  112. Zhang M et al (2008) Expression, activity, and pro-hypertrophic effects of PDE5A in cardiac myocytes. Cell Signal 20:2231–2236PubMedPubMedCentralCrossRefGoogle Scholar
  113. Zhang M et al (2010) Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5. J Am Coll Cardiol 56:2021–2030PubMedPubMedCentralCrossRefGoogle Scholar
  114. Zhao CY, Greenstein JL, Winslow RL (2016) Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network. J Mol Cell Cardiol 91:215–227PubMedPubMedCentralCrossRefGoogle Scholar
  115. Zoccarato A et al (2015) Cardiac hypertrophy is inhibited by a local pool of cAMP regulated by phosphodiesterase 2. Circ Res 117:707–719PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of Cardiology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Pharmacology and Molecular SciencesJohns Hopkins University School of MedicineBaltimoreUSA

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