Phosphodiesterases and cardiac cGMP: evolving roles and controversies

Abstract

cGMP and its primary target kinase, protein kinase G (PKG), are well recognized modulators of cardiac function and the chronic stress response. Their enhancement appears to serve as a myocardial brake, reducing maladaptive hypertrophy, improving cell survival, signaling and mitochondrial function, protecting against ischemia/reperfusion injury, and blunting the stimulatory effects of catecholamines. Translation of these effects into a chronic treatment for patients with heart failure based on increasing the generation of cGMP has been difficult, however, with tolerance and hypotension effects occurring with nitrates and neutral responses to natriuretic peptides (at least B-type). Inhibition of cGMP-targeted phosphodiesterases (PDEs) such as PDE5A is an alternative approach that appears to have more potent effects. Recent studies in experimental models and patients are revealing benefits in heart failure syndromes, and ongoing multicenter trials are testing the efficacy of PDE5A inhibition. In this review we discuss recent research findings and controversies regarding the PDE/cGMP/PKG signaling pathway, and suggest directions for further research.

Figure 1. Schematic diagram showing PDE/PKG regulation of cardiac myocytes

Generation of cGMP is shown from both a nitric oxide synthase (NOS) –soluble guanylate cyclase (sGC) pathway, and natriuretic peptide receptor-receptor GC pathway. These are two very different pools, and appear to regulate different aspects of cardiac myocyte function and stress adapatation. Their stimulated PKG is also likely compartmentalized though this remains to be clarified and is depicted here for simplicity as a common pool. Once generated, cGMP can stimulate its effecter kinase PKG, and also regulates and is regulated by phosphodiesterases. Four PDEs (PDE1a, c; PDE2, PDE3a, and PDE5a) have been identified as contributing to hydrolytic regulation and/or signaling in myocytes. PDE1 is calcium-calmodulin (CaM) dependent and is a dual esterase, PDE2 is a cGMP-stimulated cAMP esterase, while PDE3A is principally a cAMP esterase that can be competitively inhibited by cGMP. PDE5a is the only selective cGMP esterase of this group. It has several post-translational activation mechanisms; cGMP binding to N-terminus GAF domains, and PKG phosphorylation at serine 92. On the right of the figure are the targets of PKG. PKG can activate PDE5a – to lower cGMP, but may also target the rGC/NPR complex to stimulate cGMP generation, PKG also phosphorylates phospholamban (PLB) to enhance calcium uptake by the sarcoplasmic reticulum (SR), and mitochondrial proteins to regulate K_ATP channel opening and provide cardioprotection. Recent studies have also shown revealed it phosphoryates and binds to regulator of G-coupled protein signaling RGS2 and RGS4, both acting to suppress Gαq-coupled signaling cascades (e.g. Ras, MAP kinase, CamKII, and associated transcription factors, NFAT, MEF2 and GATA-4) Studies have also shown PKG directly phosphorylates and suppresses transient receptor potential channel 6, reducing the trigger calcium that has been linked to calcineurin (Cn) activation and subsequent dephosphorylation of NFAT, leading to the latter’s nuclear translocation.