Hydrogen sulphide (H2S) is increasingly being recognized as an important signalling molecule in the cardiovascular and nervous systems. The production of H2S from L-cysteine is catalysed primarily by two enzymes, cystathionine gamma-lyase and cystathionine beta-synthase. Evidence is accumulating to demonstrate that inhibitors of H2S production or therapeutic H2S donor compounds exert significant effects in various animal models of inflammation, reperfusion injury and circulatory shock. H2S can also induce a reversible state of hypothermia and suspended-animation-like state in rodents. This article overviews the physiology and biochemistry of H2S, summarizes the effects of H2S inhibitors or H2S donors in animal models of disease and outlines the potential options for the therapeutic exploitation of H2S.

Hydrogen sulphide and its therapeutic potential

The important life-supporting role of hydrogen sulfide (H2S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H2S had only been known for its toxicity and environmental hazard. Physiological importance of H2S has been appreciated for about a decade. It started by the discovery of endogenous H2S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H2S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H2S. The physiological functions of H2S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H2S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes...

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Physiological Implications of Hydrogen Sulfide: A Whiff Exploration That Blossomed

Reactive oxygen, nitrogen, and sulfur species, referred to as ROS, RNS, and RSS, respectively, are produced during normal cell function and in response to various stimuli. An imbalance in the metabolism of these reactive intermediates results in the phenomenon known as oxidative stress. If left unchecked, oxidative molecules can inflict damage on all classes of biological macromolecules and eventually lead to cell death. Indeed, sustained elevated levels of reactive species have been implicated in the etiology (e.g., atherosclerosis, hypertension, diabetes) or the progression (e.g., stroke, cancer, and neurodegenerative disorders) of a number of human diseases.1 Over the past several decades, however, a new paradigm has emerged in which the aforementioned species have also been shown to function as targeted, intracellular second messengers with regulatory roles in an array of physiological processes.2 Against this backdrop, it is not surprising that considerable ongoing efforts are aimed at elucidating the role that these reactive intermediates play in health and disease.

Site-specific, covalent modification of proteins represents a prominent molecular mechanism for transforming an oxidant signal into a biological response. Amino acids that are candidates for reversible modification include cysteines whose thiol (i.e., sulfhydryl) side chain is deprotonated at physiological pH, which is an important attribute for enhancing reactivity. While reactive species can modify other amino acids (e.g., histidine, methionine, tryptophan, and tyrosine), this Review will focus exclusively on cysteine, whose identity as cellular target or “sensor” of reactive intermediates is most prevalent and established.3 Oxidation of thiols results in a range of sulfur-containing products, not just disulfide bridges, as typically presented in biochemistry textbooks. An overview of the most relevant forms of oxidized sulfur species found in vivo is presented in Chart 1.






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Chart 1

Biologically Relevant Cysteine Chemotypesa

aRed, irreversible modifications. Green, unique enzyme intermediates. Note: Additional modifications can form as enzyme intermediates including thiyl radicals, disulfides, and persulfides.

Cysteine-Mediated Redox Signaling: Chemistry, Biology, and Tools for Discovery

Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Although the translation of ischemic postconditioning and remote ischemic conditioning protocols to patients with acute myocardial infarction has been fairly successful, the pharmacological recruitment of cardioprotective signaling has been largely disappointing to date.

Molecular Basis of Cardioprotection: Signal Transduction in Ischemic Pre-, Post-, and Remote Conditioning

Rationale: The recent emergence of hydrogen sulfide (H2S) as a potent cardioprotective signaling molecule necessitates the elucidation of its cytoprotective mechanisms.

Objective: The present study evaluated potential mechanisms of H2S-mediated cardioprotection using an in vivo model of pharmacological preconditioning.

Methods and Results: H2S (100 μg/kg) or vehicle was administered to mice via an intravenous injection 24 hours before myocardial ischemia. Treated and untreated mice were then subjected to 45 minutes of myocardial ischemia followed by reperfusion for up to 24 hours, during which time the extent of myocardial infarction was evaluated, circulating troponin I levels were measured, and the degree of oxidative stress was evaluated. In separate studies, myocardial tissue was collected from treated and untreated mice during the early (30 minutes and 2 hours) and late (24 hours) preconditioning periods to evaluate potential cellular targets of H2S. Initial studies revealed that H2S provided profound protection against ischemic injury as evidenced by significant decreases in infarct size, circulating troponin I levels, and oxidative stress. During the early preconditioning period, H2S increased the nuclear localization of Nrf2, a transcription factor that regulates the gene expression of a number of antioxidants and increased the phosphorylation of protein kinase Ce and STAT-3. During the late preconditioning period, H2S increased the expression of antioxidants (heme oxygenase-1 and thioredoxin 1), increased the expression of heat shock protein 90, heat shock protein 70, Bcl-2, Bcl-xL, and cyclooxygenase-2 and also inactivated the proapoptogen Bad.

Conclusions: These results reveal that the cardioprotective effects of H2S are mediated in large part by a combination of antioxidant and antiapoptotic signaling.

Hydrogen Sulfide Mediates Cardioprotection Through Nrf2 Signaling

Endogenous H(2)S is synthesized mainly by cystathionine gamma-lyase in the heart. The present study investigated the role of H(2)S in cardioprotection induced by ischemic preconditioning. We have examined the effect of endogenous H(2)S and exogenous application of NaHS (H(2)S donor) on cardiac rhythm in the isolated rat heart subjected to low-flow ischemia insults as well as cell viability and function in isolated myocytes exposed to simulated ischemia solution. Preconditioning with NaHS (SP) or ischemia (IP) for three cycles (3 min each cycle separated by 5 min of recovery) significantly decreased the duration and severity of ischemia/reperfusion-induced arrhythmias in the isolated heart while increasing cell viability and the amplitude of electrically induced calcium transients after ischemia/reperfusion in cardiac myocytes. Both IP and SP also significantly attenuated the decreased H(2)S production during ischemia. Moreover, decreasing endogenous H(2)S production significantly attenuated the protective effect of IP in both the isolated heart and isolated cardiac myocytes. Blockade of protein kinase C with chelerythrine or bisindolylmaleimide I as well as ATP-sensitive K(+) (K(ATP)) channel with glibenclamide (a nonselective K(ATP) blocker) and HMR-1098 (1-[[5-[2-(5-Chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea) (a sarcolemmal K(ATP) channel blocker) reversed the cardioprotection induced by SP or IP. However, blockade of mitochondrial K(ATP) channels with 5-hydroxydecanoic acid had no effect on the cardioprotection of SP, suggesting that, unlike the mechanism involved in IP, mitochondrial K(ATP) channels most probably do not play a major role in the cardioprotection of SP. Our findings suggest that endogenous H(2)S contributes to cardioprotection induced by IP, which effect may involve protein kinase C and sarcolemmal K(ATP) channels.

Zhan-Ning Feng

Papers

Role of Hydrogen Sulfide in the Cardioprotection Caused by Ischemic Preconditioning in the Rat Heart and Cardiac Myocytes

Endogenous hydrogen sulfide contributes to the cardioprotection by metabolic inhibition preconditioning in the rat ventricular myocytes.