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. Author manuscript; available in PMC: 2015 Dec 2.
Published in final edited form as: Basic Res Cardiol. 2015 Aug 30;110(5):510. doi: 10.1007/s00395-015-0510-9

Hydrogen sulfide and PKG in ischemia-reperfusion injury: sources, signaling, accelerators and brakes

Ioanna Andreadou 1, Efstathios K Iliodromitis 2, Csaba Szabo 3, Andreas Papapetropoulos 1,4
PMCID: PMC4667708  NIHMSID: NIHMS740232  PMID: 26318600

Abstract

Over the past decade, hydrogen sulfide has emerged as an important cardioprotective molecule with potential for clinical applications. Although several pathways have been proposed to mediate the beneficial effects of H2S, the NO and cGMP axis has attracted significant attention. Recent evidence has suggested that cGMP-dependent protein kinase can lie both downstream and upstream of H2S. The current literature on this topic is reviewed and data from recent studies are integrated to propose a unifying model.

Introduction

Hydrogen sulfide (H2S) was initially of interest solely to toxicologists that have been studying its biohazardous properties for decades. The first study to propose that H2S could be an endogenous signaling molecule in mammalian cells serving neuromodulator functions was reported in 1996 (Abe, 1996). Soon after that, the same group described the role of H2S as a mediator of vasorelaxation (Hosoki, 1997). A steady interest for the role of H2S in physiology and disease has been noted since. H2S is produced by three different enzymes, namely cystathionine gamma-lyase (CSE), cystathionine beta-synthase (CBS), and 3-mercatopyruvate sulfurtransferase (3-MST) (Wang 2012), all of which are expressed in the heart (Kondo 2012). In spite of the lack of detailed studies on the relative level of expression of CBS, CSE and 3MST in different vascular beds and in the myocardium, it is claimed that CSE is the predominant source of enzymatically derived H2S in the cardiovascular system. In the heart, this is true as H2S levels are reduced by 80% in CSE KO mice (King 2014). To deliver H2S to cells, a number of donor compounds have been developed that differ in the mode and rate of H2S release (Papapetropoulos 2015). Most studies have been performed using H2S salts (NaHS or Na2S) that are gradually being replaced by agents that more slowly release H2S, mimicking the endogenous generation of this gasotransmitter.

H2S and cardioprotection

Both endogenously produced and exogenously supplied H2S exhibit cardioprotective actions [Andreadou 2015, Predmore 2011, Wang 2012, Szabo 2011, Polhemus 2014). While no studies on the role of CBS or 3MST in the heart have been published so far, mice with targeted disruption of the CSE gene locus are more susceptible to myocardial damage after left coronary artery ligation (King 2014). In contrast, mice over expressing CSE in their cardiomyocytes exhibit greater degree of protection against ischemia-reperfusion injury (Elrod 2007). Pharmacological treatment with H2S donors in ischemia-reperfusion injury models applied either at the time of reperfusion or as a preconditioning agent, preserves mitochondrial respiration, attenuates the expression of inflammatory cytokines, inhibits leukocyte recruitment, reduces oxidative stress levels, improves left ventricular function and reduces myocardial infarct size (Bian 2006; Bibli 2015; Calvert, 2009; Calvert 2010; Elrod, 2007; Sivarajah, 2009; Sivarajah, 2006). Improved myocardial survival and function has also been noted with H2S donors in heart failure and cardiomyopathy models (Wang 2012, Polhemus 2014). Although the role of H2S as a cardioprotective molecule is well-established, the signaling pathways mediating its effects are still under investigation. As efforts are under way to harness the therapeutic potential of H2S (Wallace and Wang, 2015), the dosing scheme (chronic vs acute H2S administration and timing of H2S application), as well as the choice of donors to be used for cardioprotection, are important issues to consider if drug development efforts are to come to fruition. Due to the importance of the NO/cGMP pathway in attenuating I/R injury (Andreadou 2015, Garcia-Dorado 2009) and based on the contribution of NO to the cardioprotective action of H2S (Bibli 2015, King 2014), herein we will focus on the interaction between H2S, cGMP and its target kinase, cGMP-dependent protein kinase G in animal model of myocardial infarction.

Interplay between NO and H2S

Ample evidence for a cross-talk between H2S and the endothelial NO pathway exists with most of the evidence pointing towards a synergistic action of the two gasotransmitters. H2S enhances Akt activity (Papapetropoulos 2009), possibly through PTEN inhibition (Greiner 2014), triggering eNOS phosphorylation on Ser1177 and increased NO production (Coletta 2012, King 2014). At the same time, H2S serves as a potent and selective PDE5 inhibitor, exhibiting a 30-fold selectivity for PDE5 over other PDEs (Bucci 2010, Panopoulos 2015). Moreover, H2S also prevents nitrosation of eNOS on Cys443 keeping it in the active, dimeric form (Altaany 2014). H2S also keeps the soluble guanylyl cyclase, the NO “receptor”, in its ferrous, NO-responsive form (Zhou 2015).

At the functional level, it has been demonstrated that the actions of H2S and NO are mutually dependent in the vessel wall, as inhibition of the production of one gasotransmitter abolishes or reduces angiogenesis and vascular relaxation triggered by the other (Coletta 2012). The interaction between H2S and NO has been confirmed to occur in the heart, where H2S donor administration resulted in increased eNOS phosphorylation and enhanced NO availability leading to cardioprotection in myocardial infarction, heart failure and cardiac arrest models; the H2S protective effects were abolished in eNOS KO mice (Polhemus, 2013; Kondo, 2013, King, 2014; Bibli 2015, Minamishima 2009).

H2S signaling and PKG

A role for cGMP-dependent protein kinase (PKG) in H2S signaling has been reported in vascular cells. It was shown that exposure of endothelial cells or vessels to NaHS led to increased cGMP accumulation and activation of PKG, as suggested by an increase in VASP phosphorylation, a surrogate marker of its activity (Coletta, 2012). Both vasorelaxation and angiogenic responses to NaHS (proliferation, migration, network formation) were attenuated by the PKG-Iα inhibitor DT-2 (Coletta 2012, Bucci 2012). Moreover, L-cysteine- and NaHS-induced relaxations in mouse aortas from PKG-I KO mice were reduced compared to wild-type controls, reinforcing the notion that PKG is an integral part of H2S signaling (Bucci, 2012). Activation of PKG-I was also shown to mediate the effects of NaHS in vivo, since pretreatment of mice with DT-2 abolished the hypotensive response to NaHS (Bucci, 2012).

PKG in the heart lies downstream of H2S

We have recently shown that bolus administration of NaHS at the end of prolonged ischemia (and prior to reperfusion) leads to increased cardiac cGMP levels and PKG activation. In both rabbits and mice, the cardioprotective effect exhibited by the acute administration of NaHS was reduced by DT-2 (Bibli 2015). In the same study, we identified phospholamban (PLN) as a downstream target of PKG. PLN once phosphorylated reduces free intracellular Ca2+ concentration by dissociating from SERCA allowing it to pump Ca2+ ions back into the sarcoplasmic reticulum (Kranias, 2012), limiting the damage from hypercontracture and mPTP opening. Additional downstream targets for PKG in cardiomyocytes ameliorating I/R injury have been reported and include among others the Na/H exchanger and the mitochondrial KATP channels, which are direct H2S targets (Dorado 2009; Heusch 2015; Inserte 2011). It should be kept in mind that PKG-independent cardioprotective pathways of NO also exist (Chouchani 2013; Cohen 2010; Methner 2013). Moreover, it should be noted that cGMP-independent activation of PKG by NaHS has also been reported. NaHS will form polysulfides in the presence of oxygen, which in turn catalyze the formation of an activating interprotein disulfide within PKG-Iα, trigerring vasorelaxation and lowering blood pressure (Stubbert 2014). Transgenic knockin mice in which the cysteine 42 redox sensor of PKG has been replaced by serine, exhibit reduced responses to NaHS.

PKG can also lie downstream of H2S in the heart

Earlier studies had shown that treatment with the PDE5 inhibitor taladafil one hour prior to coronary artery ligation, results in increased H2S production, reduced infarct size and preserved LV contractility. The reduction in infarct size by tadalafil was abolished in CSE KO mice or following PKG or CSE pharmacological inhibition (Salloum 2009). In a similar experimental set up, administration of the sGC activator, cinaciguat, increased PKG activity, CSE expression, cardiac H2S levels, ameliorated cardiac function and reduced infarct size (Salloum 2012). The above parameters were reversed by a PKG or a CSE inhibitor.

In a recent issue of this journal it was demonstrated that adenovirus-mediated gene transfer of PKG-Iα protects against ischemia/reperfusion injury through up regulation of CSE expression in cultured cardiomyocytes, as well as in vivo; CBS ad 3MST levels remained unaltered by such treatment. Inhibition of CSE with PAG, reduced H2S levels, augmented LDH release and trypan blue staining in cardiomyocytes. In vivo, PAG reversed the beneficial effects of PKG-Iα over expression (Das, 2015).

Avoiding excessive H2S production

After combining the observations made in the experiments exposing cardiac tissue to H2S donors with those made using cGMP-elevating agents and PKG over expression, one would expect that a feed-forward, self-perpetuating cycle is established. H2S would increase PKG activity and this would up regulate CSE, leading to more H2S production and greater PKG activation. Examples were treatment with H2S releasing agents leads to increased CSE expression have been reported in the literature (Bucci 2014, Tsai 2015). The ability of exogenously supplied H2S to augment endogenous H2S production is in stark contrast to most agonists or enzyme activators cause down regulation of their cognate receptors or targets. If this positive feedback loop indeed existed, H2S levels would constantly increase over time reaching toxic H2S levels. It is well known that H2S in high concentrations is deleterious as it inhibits cytochrome c oxidase, acting as a respiratory chain poison (Wang 2012). Thus, the need for a brake that would prevent cells from accumulating toxic H2S concentrations becomes apparent. The brake might come in the form of a posttranslational modification, such as the one reported very recently by Yuan et al. These authors demonstrated that CSE is a PKG substate; phosphorylation of CSE by PKG on Ser377, inhibits its activity by 75% (Yuan, 2015).

H2S, CSE and ischemia

Under normoxic conditions, cells oxidize H2S in the mitochondria to thiosulfate and then sulfate, thereby maintaining a low intracellular H2S concentration (Olson, 2012, Banerjee 2014). As oxygen levels fall during ischemia, H2S oxidation begins to fail and intracellular H2S increases. At the same time, in spite of the presumably higher tissue levels of H2S, several studies in different animal models have shown a gradual decrease in myocardial cGMP content during ischemia (Garcia-Dorado 2009). A drop in cGMP levels will translate into lower PKG activity, leading to reduced CSE phosphorylation and enhanced H2S output. Thus, H2S levels during ischemia would be expected to rise both due to increased production and limited degradation. As long as some oxygen is present to act as end acceptor, H2S will serve as an electron donor for the respiratory chain (Modis 2013) becoming an energy fuel and preserving ATP levels. The above mentioned observations are entirely speculative and need to be experimentally confirmed, but for the time being provide a rational as to why endogenously produced H2S during ischemia is beneficial.

Conclusion

The NO/cGMP pathway is an integral part of H2S signaling in the cardiovascular system. Several levels of interaction between NO and H2S have been established to occur and more links between H2S, PKG and CSE are emerging. These interactions are complex and require intense experimental effort to prove their functional consequences and relevance to different cardiac diseases. Understanding the molecular mechanisms of action of H2S donors will help design better treatment regiments and target appropriate pathological conditions to capitalize on the progress made in H2S biology for the benefit of patients.

Figure 1.

Figure 1

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Cross-talk and interactions between H2S and PKG pathways in cardiac myocytes. Exposure of cardiomyocytes to H2S donors (or endogenously produced H2S) leads to increased cGMP levels through activation of eNOS and/or PDE inhibition. Increased cGMP-dependent protein kinase activity results in upregulation of CSE levels and H2S production, that further increases cGMP levels and PKG activity. Phosphorylation and inhibition of CSE by PKG serves as a brakε to control H2S output.

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: Aristeia 2011 (1436) to AP.

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