Cardiac Cyclic Nucleotide Phosphodiesterases: Roles and Therapeutic Potential in Heart Failure

Figures

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  Fig. 1. Cyclic nucleotide signalling within cardiomyocytes. Cyclic adenosine-3′,5′-monophosphate (cAMP) is synthesised from adenosine-5′-triphosphate (ATP) by the action of adenylyl cyclases (ACs) in response to noradrenaline (NA). Cyclic guanosine-3′,5′-monophosphate (cGMP) is synthesised from guanosine-5′-triphosphate (GTP) by the action of guanylyl cyclases (GCs). GC-1/2 is stimulated by nitric oxide (NO) and is primarily located within the cytosol. Transmembrane GC-A is activated by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and GC-B is triggered by C-type natriuretic peptide (CNP). cAMP and cGMP act predominantly via activation of protein kinase A (PKA) and protein kinase G (PKG), respectfully. cAMP also binds exchange protein activated by cAMP (EPAC). Both PKA and PKG phosphorylate multiple cardiomyocyte proteins to effect changes in chronotropy, inotropy and lusitropy, as well as cardiomyocyte hypertrophy and apoptosis. Arrows indicate stimulation. Blunt lines indicate inhibition. Abbreviations: [Ca2+]i, intracellular concentration of calcium; β-AR, beta-adrenergic receptor; Ca2+, calcium; CaM, calmodulin; cMYBPC, cardiac myosin–binding protein C; cTnI,…

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  Fig. 2. Phosphodiesterase regulation of cyclic nucleotides within cardiomyocytes. Phosphodiesterases (PDEs) catalyse the hydrolysis and inactivation of cyclic adenosine-3′,5′-monophosphate (cAMP) and cyclic guanosine-3′,5′-monophosphate (cGMP) forming adenosine monophosphate (AMP) and guanosine monophosphate (GMP), respectively. PDEs 1, 2, 3, 4, 5 and 9 are the principal regulators of cAMP and cGMP signalling in cardiomyocytes. PDE1 is calcium/calmodulin (Ca2+/CaM)-dependent and hydrolyses cAMP and cGMP. PDE2 is stimulated by cGMP binding to its GAF-B domain. PDE2 degrades cAMP and cGMP, and there is evidence that PDE2 hydrolyses both the natriuretic peptide (NP) and the nitric oxide (NO) pools of cGMP. PDE3 is a dual esterase but is inhibited by cGMP, and PDE4 is cAMP-selective. PDE5 is stimulated by cGMP binding to its GAF-A domain and largely hydrolyses NO/cGMP. PDE9 metabolises NP/cGMP. Abbreviations: AC, adenylyl cyclase; ANP, atrial natriuretic peptide; ATP, adenosine-5′-triphosphate; β-AR, beta-adrenergic receptor; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide; GAF, cGMP-stimulated PDE, Anabaena AC and Fhla transcription factor; GC, guanylyl cyclase; GTP,…

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  Fig. 3. Structures of phosphodiesterases 1–5. Phosphodiesterase (PDE) 1 contains two calmodulin (CaM) binding domains, two phosphorylation sites and an inhibitory (I) region. PDE2 and PDE5 possess two cGMP-stimulated PDE, Anabaena AC and Fhla transcription factor (GAF) domains. Binding of cyclic guanosine-3′,5′-monophosphate (cGMP) to GAF-B and GAF-A stimulates the hydrolytic activity of PDE2 and PDE5, respectively. PDE3 can be phosphorylated at multiple regions, and PDE4 contains one phosphorylation site within its first upstream conserved regions (UCRs). Abbreviations: C, carboxyl-terminus; N, amino terminus; P, phosphate

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  Fig. 4. Changes in cardiac phosphodiesterase expression during heart failure and pharmacological modulators. Phosphodiesterases (PDEs) 1, 2, 3, 4, 5 and 9 contribute to the pathophysiology of heart failure (HF). Arrows indicate changes in PDE expression during HF. Blunt lines indicate inhibition with selective pharmacological modulators