Deciphering the Dynamics and Therapeutic Potential of the Cardiac cGMP Cascade: An Update on Where We Are and What We Need to Know
2020-02-27

Based on substantial evidence, the 3′,5′-cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase type I (cGKI aka PKGI) signaling dyad is appreciated as an endogenous counterweight to the sympathetic and renin–angiotensin–aldosterone systems with antihypertrophic and/or antifibrotic properties, as well as ischemia and reperfusion injury and cell death opposing actions in the heart. Yet harnessing the cardioprotective potential of the associated pathway(s), that is, its generators and effectors, in different cardiac cell types has proven for the most part to be elusive. Seven review articles in the May and June issues of the Journal of Cardiovascular Pharmacology discuss what is currently known about cGMP/PKGI signaling in the heart and, importantly, highlight the pressing issues that still wait to be resolved. Adrian J. Hobbs et al lead off the series and present a comprehensive overview of the nitric oxide (NO) and natriuretic peptide (NP) arms of cGMP/PKGI signaling in the normal and diseased heart.1 Their overview presents evidence of what can in fact go wrong to compromise signaling or diminish its utility. This would include, among others, oxidation of key signaling components, the complicated interplay between signaling pathways, and the potential hypotension that challenges the straightforward exploitation of agents that modulate cGMP/PKGI signaling. Blanton2 delves further into potential reasons for the failures of cGMP-augmenting drugs in heart failure. Besides the loss of NO and NO synthase 3 (NOS3) and changes in the NO-sensitive (soluble) guanylyl cyclase (NO-GC) redox state, his article discusses alterations in the processing of atrial NP and B-type NP and changes in the expression levels of NP receptor A, NPR-B, and NPR-C receptors, as well as increased neprilysin expression. Blanton also addresses the oxidative modification of cardiac PKGIα, which leads to its constitutive activation and its altered subcellular distribution. Unresolved are the questions of PKGI isoforms and cellular specificity, as well as the multiple targets of PKGI, which evidence redundancy or actions that might be antithetical to the desired outcome. Finally, he discusses the reasons why so far clinical trials designed to harness the potential of cardiac cGMP signaling may have failed. In the review by Cuello and Nikolaev,3 they focus on the challenges of studying the local actions of drugs that elevate cGMP at the subcellular level, to encourage the development of novel therapeutic approaches and further understand the regulation of PKGI signaling. Their article discusses the use of fluorescent biosensors that are able to monitor cGMP levels at specific subcellular locations with a high degree of spatial and temporal resolution. These emerging new tools have greatly enhanced our knowledge of cGMP signaling in the healthy and diseased cardiomyocyte and heart. Their article also addresses future challenges for cGMP-based medications in heart failure patients (both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction) and underscores the need for a better understanding of the molecular aspects of cGMP compartmentation and microdomain-specific regulation, in the healthy and diseased patients, to develop improved and individualized therapies. An alternative strategy to increase cGMP levels is to inhibit its breakdown by cyclic nucleotide phosphodiesterases (PDEs). In the contribution by Dunkerly-Eyring and Kass,4 they provide a detailed overview of the 5 PDEs in cardiac myocytes that are capable of hydrolyzing cGMP and are shown to have a role in cardiac pathophysiology. PDE1, PDE2, and PDE3 also breakdown cAMP, whereas PDE5 and PDE9 are selective for cGMP. The authors provide insights into the challenges and benefits of selectively targeting these PDEs. For instance, PDE3 inhibitors are already in clinical use to treat acute decompensated heart failure, and in the future, isoform-specific PDE3 modulation may ensure their safe and long-term use. Their review considers the utility of inhibitors against the cGMP-hydrolyzing PDEs, as well as their cellular and subcellular compartmentation, differential control over NO-generated versus NP-generated cGMP, and coupling to different outcomes, whereas the latter may be complicated by multiple actions of the different PDE isoforms involved as well as the crosstalk between them. Lukowski and his group summarize current knowledge about PKGI targets in cardiomyocytes and their pathophysiological functions.5 Included are sarcomeric proteins regulating contraction, calcium-handling proteins, signaling proteins, transcription factors controlling gene expression, and novel mitochondrial targets of NO-GC/cGMP, such as the Ca2+-activated and voltage-activated K+ channel BK.6,7 An area ripe for exploration is the regulation of endogenous proteins that anchor PKG (GKAPs) within protein networks at specific locations within the cardiomyocyte. As discussed by the authors of this article, a better appreciation of these downstream targets could be exploited to define novel therapeutic strategies that may remain “intact” in the face of impaired or dysregulated upstream cGMP signaling. Miyazaki and Ichinose8 address the utility of therapeutic interventions that increase vascular NO bioavailability to treat cardiac arrest complicated by postcardiac arrest syndrome (PCAS). Many survivors of cardiac arrest suffer irreversible neurological deficits due to widespread endothelial dysfunction that is associated with platelet activation and systemic inflammation. These authors present the case that the augmentation of NO bioavailability using several strategies, most notably NO inhalation (iNO) therapy, improves neurological outcomes and survival after cardiac arrest/PCAS. The basis for the benefit of iNO therapy is not fully clear but, as indicated by Miyazaki and Ichinose, may involve attenuation of hemoglobin-mediated plasma NO consumption. Alternative pharmacological approaches to increase NO bioavailability in cardiac arrest/PCAS include inhibiting S-nitrosoglutathione reductase or administrating sodium nitrite. Recent novel findings from genome-wide association studies and exome sequencing studies have revealed new aspects of NO/cGMP signaling that have renewed interest in exploiting NO/cGMP signaling as a therapeutic target in cardiovascular diseases. The contribution of Thomas Kessler and colleagues presents recent genetic evidence linking cGMP-related signaling constituents to coronary artery disease/myocardial infarction, namely, NOS3, GUCY1A1, PDE5A, MRVI1, and PDE3A, as well as EDN1.9 Kessler et al discuss the functional basis for and translational implications of this association, and the possibility that it may help in guiding future treatment strategies. We trust that our readers will find this timely review series on cGMP/PKG both insightful and provocative. The articles presented differ as far as what aspects of cGMP/PKGI signaling are covered. However, they are alike in highlighting recent findings and unanswered questions and heralding the untapped potential of this signaling pathway, that is, its different facets, in preventing and/or treating cardiovascular diseases.