Abstract
Cardiac contractility is regulated by several neural, hormonal, paracrine, and autocrine factors. Amongst these, signaling through β-adrenergic and serotonin receptors generates the second messenger cyclic AMP (cAMP), whereas activation of natriuretic peptide receptors and soluble guanylyl cyclases generates cyclic GMP (cGMP). Both cyclic nucleotides regulate cardiac contractility through several mechanisms. Phosphodiesterases (PDEs) are enzymes that degrade cAMP and cGMP and therefore determine the dynamics of their downstream effects. In addition, the intracellular localization of the different PDEs may contribute to regulation of compartmented signaling of cAMP and cGMP. In this review, we will focus on the role of PDEs in regulating contractility and evaluate changes in heart failure.
Highlights
Phosphodiesterases (PDEs) are the enzymes that degrade both cyclic adenosine 30,50 monophosphate and cyclic guanosine 30,50 -monophosphate to nucleoside phosphates (50 AMP and 50 GMP, respectively)
We focus on the role of PDEs in regulating cardiac contractility (Figure 1)
The natriuretic peptide C-type natriuretic peptide (CNP) can modulate contractility by affecting cAMP signaling through cGMP-mediated inhibition of PDE3, causing a positive inotropic response (PIR) mediated by β1 -adrenergic receptor (β1 -AR) and β2 -AR in normal and failing rat left ventricle [53,62,98]. 5-HT4 receptor-induced PIR
Summary
Phosphodiesterases (PDEs) are the enzymes that degrade both cyclic adenosine 30 ,50 monophosphate (cAMP) and cyclic guanosine 30 ,50 -monophosphate (cGMP) to nucleoside phosphates (50 AMP and 50 GMP, respectively). Global and local cGMP are degraded by PDE2 and phosphorylates These pool events contribute a negative triggers a more (orange) whichtodoes not PDE3. Increasing an NO‐dependent cGMP pool which activates PDE2 and decreases β1/2‐AR‐stimulated cAMP/cGMP cross-talk is illustrated with black arrows indicating cGMP activation of PDE2 or contractility. This pool of cGMP (yellow) is degraded by PDE2 and PDE5. 0 ,50 -monophosphate; CNP, C-type natriuretic peptide; EP, cAMP/cGMP, cyclic adenosine/guanosine nase A/G; RyR, ryanodine receptor; SERCA, sarcoendoplasmic reticulum (SR) calcium ATPase; prostanoid receptor; GC-A/B, cyclase. L-type calcium channel; NA, noradrenaline; NO, nitric oxide; NOS, nitric oxide synthases; p, indicates phosphorylation; PDE, phosphodiesterase; PgE1 , prostaglandin E1 ; PKA/PKG, protein kinase A/G; 2. I; β-AR, beta-adrenergic receptor. and Created with BioRender.com, tain contractile structures accessed on 7 February
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