Role of cGMP in hydrogen sulfide signaling

doi:10.1016/j.niox.2014.12.004

Nitric Oxide

Volume 46, 30 April 2015, Pages 7-13

https://doi.org/10.1016/j.niox.2014.12.004 Get rights and content

Highlights

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H₂S donors and endogenous H₂S increase cGMP.
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This is achieved by PDE inhibition, eNOS activation or increased NO bioavailability.
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H₂S is a non-selective PDE inhibitor.
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Rate of H₂S release determines the concentration of donor needed to increase cGMP.
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Donors with faster release rates are more likely to exert their effects through cGMP.

Abstract

The importance of hydrogen sulfide (H₂S) in physiology and disease is being increasingly recognized in recent years. Unlike nitric oxide (NO) that signals mainly through soluble guanyl cyclase (sGC)/cGMP, H₂S is more promiscuous, affecting multiple pathways. It interacts with ion channels, enzymes, transcription factors and receptors. It was originally reported that H₂S does not alter the levels of cyclic nucleotides. More recent publications, however, have shown increases in intracellular cGMP following exposure of cells or tissues to exogenously administered or endogenously produced H₂S. Herein, we discuss the evidence for the participation of cGMP in H₂S signaling and reconcile the seemingly divergent results presented in the literature on the role of this cyclic nucleotide in the biological actions of H₂S.

Introduction

Initial observations about the presence of H₂S in mammalian tissues were overlooked as it was thought to be metabolic waste, rather than a molecule of biological significance [1]. It is now known that H₂S is produced by two enzymes of the transulfuration pathway cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), as well as by the concerted action of cysteine aminotransferase (CAT) or D-amino acid oxidase (DAO) and 3-mercaptopyruvate sulfurtransferase (MST) [2], [3].

Endogenously produced H₂S is a signaling molecule which participates in the regulation of various physiological processes in the cardiovascular, nervous, endocrine, reproductive gastrointestinal and immune systems [1], [4], [5], [6], [7]. Deregulated H₂S production is observed in many pathological conditions including atherosclerosis, hypertension, heart failure, diabetes, cirrhosis, inflammation, sepsis, neurodegenerative disease, erectile dysfunction, and asthma [1], [8], [9], [10], [11], [12]. In these conditions, H₂S either participates in the pathogenesis or affects the course of the disease.

To exert its many effects in physiology and disease, H₂S utilizes a variety of signaling pathways. H₂S affects many cellular redox processes and alters the activity of ion channels (potassium, calcium and chloride), kinases, phosphatases and transcription factors [1], [5], [6], [7], [11], [13]. Many of these effects do not require the participation of a second messenger, but rather result from S-sulfhydration [6]. For example, H₂S has been shown to increase K_ATP channel activity by sulfhydrating both SUR1 and Kir6.1 (the pore-forming subunit) [14], [15]. In addition, H₂S activates nuclear factor erythroid 2-related factor 2 (Nrf-2) by sulfhydrating Kelch-like ECH-associated protein 1 (Keap1) and disrupting the Nrf-2/Keap1 complex; Keap1 binding to Nrf-2 sequesters the transcription factor in an inactive form in the cytosol [16]. H₂S also activates nuclear factor-κB (NF-κB) through sulfhydration of the p65 subunit; this enhances the binding to ribosomal protein S3, which increases p65 transcriptional activity in the nucleus [17]. In contrast to the above well-described pathways, the contribution of cyclic nucleotides to H₂S signaling remains controversial. Herein, we will review the literature on the participation of cGMP in H₂S signaling and biological activity and reconcile some of the divergent results that have appeared in recent publications.

Section snippets

Regulation of cGMP levels

Resting cGMP levels are about a tenth of those of cAMP in cells [18]; the difference in the amounts of the two second messengers was partly responsible for the delay in the growth of the cGMP field, which expanded substantially when it became apparent that it mediates nitric oxide (NO)-stimulated vasorelaxation [19]. cGMP levels inside cells are dependent on the relative rate of synthesis vs degradation. cGMP is synthesized by guanylyl cyclases (GCs) and degraded by phosphodiesterases [19], [20]

Debating the role of cGMP in H₂S responses

Early studies used a functional approach to test the contribution of cGMP to the relaxing effects of NaHS. This approach yielded mixed results. In one study, the sGC inhibitors ODQ and NS-2028 did not inhibit H₂S-induced relaxation in rat aorta; instead relaxations to H₂S were potentiated in the presence of both agents, leading the authors to the conclusion that H₂S-induced relaxation occurs independently of the cGMP pathway [28]. In addition, Cheang et al. demonstrated that in rat coronary

Implications for biological activity

So far we have summarized the existing evidence that exposure of cells to physiological amounts of endogenous H₂S or to ultra-rapid (NaHS) or fast-releasing H₂S donors (thioaminoacids) increases intracellular cGMP levels. We will next review the literature on the biological role of cGMP in H₂S-stimulated responses in vitro and in vivo. It should be mentioned that lack of inhibition of a H₂S-triggered biological effect by ODQ does not exclude the participation of cGMP-regulated pathways in any

Conclusions

To summarize, not all H₂S donors and treatment regimens have the ability to increase cGMP levels in cells. In order to access the contribution of cGMP to the effects of a particular H₂S-releasing compound one should measure the levels of this cyclic nucleotide. From the available data, ultra-fast (salts) or fast H₂S-releasing compounds (thioaminoacids) are more likely to exert their effects in a cGMP-dependent manner, compared to slow releasing H₂S donors. The increase in cGMP levels can result

Acknowledgments

This work has been co-financed by the European Union (European Social Fund) – ESF and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) – Research Funding Program: Thalis (MIS 380259); Investing in knowledge society through the European Social Fund and Aristeia 2011 (1436) to AP, by EU FP7 REGPOT CT-2011-285950 – “SEE-DRUG” and by the COST Action BM1005 (ENOG: European network on gasotransmitters).

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3) H2S may alleviate oxidative stress, resulting in increased eNOS coupling by phosphorylation of eNOSS1177 [44,45]. ( 4) The reaction of soluble guanylyl cyclases (sGCs) to NO can be enhanced by H2S [40,46]. It might be related to the reduction of sGC heme Fe by H2S, so as to facilitate NO-regulated cellular signaling processes [47].
Hydrogen sulfide (H₂S) is considered to be the third gasotransmitter after carbon monoxide (CO) and nitric oxide (NO). It plays an important role in the regulation of vascular homeostasis. Vascular remodeling have has proved to be related to the impaired H₂S generation.
This study aimed to summarize and discuss current data about the function of H₂S in vascular physiology and pathophysiology as well as the underlying mechanisms.
Endogenous hydrogen sulfide (H₂S) as a third gasotransmitter is primarily generated by the enzymatic pathways and regulated by several metabolic pathways. H₂S as a physiologic vascular regulator, inhibits proliferation, regulates its apoptosis and autophagy of vascular cells and controls the vascular tone. Accumulating evidence shows that the downregulation of H₂S pathway is involved in the pathogenesis of a variety of vascular diseases, such as hypertension, atherosclerosis and pulmonary hypertension. Alternatively, H₂S supplementation may greatly help to prevent the progression of the vascular diseases by regulating vascular tone, inhibiting vascular inflammation, protecting against oxidative stress and proliferation, and modulating vascular cell apoptosis, which has been verified in animal and cell experiments and even in the clinical investigation. Besides, H₂S system and angiotensin-converting enzyme (ACE) inhibitors play a vital role in alleviating ischemic heart disease and left ventricular dysfunction. Notably, sulfhydryl-containing ACEI inhibitor zofenopril is superior to other ACE inhibitors due to its capability of H₂S releasing, in addition to ACE inhibition. The design and application of novel H₂S donors have significant clinical implications in the treatment of vascular-related diseases. However, further research regarding the role of H₂S in vascular physiology and pathophysiology is required.
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Hydrogen sulfide (H₂S) is now recognized as an endogenous signaling gasotransmitter in mammals. It is produced by mammalian cells and tissues by various enzymes - predominantly cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) - but part of the H₂S is produced by the intestinal microbiota (colonic H₂S-producing bacteria). Here we summarize the available information on the production and functional role of H₂S in the various cell types typically associated with innate immunity (neutrophils, macrophages, dendritic cells, natural killer cells, mast cells, basophils, eosinophils) and adaptive immunity (T and B lymphocytes) under normal conditions and as it relates to the development of various inflammatory and immune diseases. Special attention is paid to the physiological and the pathophysiological aspects of the oral cavity and the colon, where the immune cells and the parenchymal cells are exposed to a special “H₂S environment” due to bacterial H₂S production. H₂S has many cellular and molecular targets. Immune cells are “surrounded” by a “cloud” of H₂S, as a result of endogenous H₂S production and exogenous production from the surrounding parenchymal cells, which, in turn, importantly regulates their viability and function. Downregulation of endogenous H₂S producing enzymes in various diseases, or genetic defects in H₂S biosynthetic enzyme systems either lead to the development of spontaneous autoimmune disease or accelerate the onset and worsen the severity of various immune-mediated diseases (e.g. autoimmune rheumatoid arthritis or asthma). Low, regulated amounts of H₂S, when therapeutically delivered by small molecule donors, improve the function of various immune cells, and protect them against dysfunction induced by various noxious stimuli (e.g. reactive oxygen species or oxidized LDL). These effects of H₂S contribute to the maintenance of immune functions, can stimulate antimicrobial defenses and can exert anti-inflammatory therapeutic effects in various diseases.
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Furthermore, the newly described H2S-NO conjugated donor named ZYZ-803 was found to act through the PKG-cGMP pathway, resulting in vasodilation [78]. A comprehensive overview on the role of cGMP in the hydrogen sulfide signaling was provided by Bibli et al. [42]. The three known gasotransmitters have several interactions, and the summation of these result in their cardiovascular effects [97].
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ReviewRole of cGMP in hydrogen sulfide signaling

Highlights

Abstract

Introduction

Section snippets

Regulation of cGMP levels

Debating the role of cGMP in H2S responses

Implications for biological activity

Conclusions

Acknowledgments

Mol. Cell

Pharmacol. Ther

Cell. Signal

Cell. Signal

Vascul. Pharmacol

Eur. J. Pharmacol

Eur. J. Pharmacol

Biochem. Pharmacol

Bioorg. Med. Chem

Placenta

Gastroenterology

Nitric Oxide

Physiological implications of hydrogen sulfide: a whiff exploration that blossomed

Physiol. Rev

Enzymology of H2S biogenesis, decay and signaling

Antioxid. Redox Signal

A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells

Nat. Commun

Production and physiological effects of hydrogen sulfide

Antioxid. Redox Signal

Hydrogen sulfide and cell signaling

Annu. Rev. Pharmacol. Toxicol

H(2)S signalling through protein sulfhydration and beyond

Nat. Rev. Mol. Cell Biol

Hydrogen sulphide and its therapeutic potential

Nat. Rev. Drug Discov

Hydrogen sulfide-based therapeutics and gastrointestinal diseases: translating physiology to treatments

Am. J. Physiol. Gastrointest. Liver Physiol

Hydrogen sulfide and erectile function: a novel therapeutic target

Nat. Rev. Urol

Hydrogen sulfide and the pathogenesis of atherosclerosis

Antioxid. Redox Signal

Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease

Circ. Res

Emerging role of hydrogen sulfide in health and disease: critical appraisal of biomarkers and pharmacological tools

Clin. Sci. (Lond.)

H2S and its role in redox signaling

Biochim. Biophys. Acta

Molecular mechanism for H(2)S-induced activation of K(ATP) channels

Antioxid. Redox Signal

Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels

Circ. Res

Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf2

Antioxid. Redox Signal

Cyclic nucleotide research – still expanding after half a century

Nat. Rev. Mol. Cell Biol

Guanylyl cyclases and signaling by cyclic GMP

Pharmacol. Rev

Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use

Pharmacol. Rev

Review
Role of cGMP in hydrogen sulfide signaling

Debating the role of cGMP in H₂S responses