The last few years have witnessed the accumulation of a mass of knowledge on the metabolism of hydrogen sulfide (H2S) and its biological and physiological functions and related pathological implications. It is well recognized now that H2S is generated in mammalian cells and is mainly catalyzed by two enzymes, cystathionine β-synthase and cystathionine γ-lyase (CSE). H2S production and metabolism are closely regulated in order to meet different cellular metabolic and functional demands. Abnormal metabolism of H2S leads to an array of disease conditions and the correction of these abnormalities provides novel avenues for prevention or treatment of these diseases. Breakthroughs in fundamental and mechanical studies on the biological effects of H2S would be considered a failure should a follow-through not occur to transform the basic sciences into clinical applications. With this consideration, ‘follow-through after breakthrough’ becomes the theme of this special issue.
The first part of this special issue focuses on recent progress in fundamental or basic research on the effects of endogenous H2S on different species, tissues and organs and their underlying cellular and molecular mechanisms. Differential effects of H2S on cell growth and survival are excellent examples for illustrating the complex roles of H2S in our bodies. In some mammalian cells, such as smooth muscle cells, H2S at physiological concentrations inhibits cell proliferation and/or promotes apoptosis, controlling the vascular remodeling process. At the same concentration range, H2S may stimulate the growth of certain types of cells, such as endothelial cells, leading to accelerated revascularization and wound healing. It is the seemingly conflicting effects of H2S that provide homeostatic balance for the structural and functional integrity of the concerned systems or organs. This also insinuates the critical importance of a cell type-based versus organ- or tissue-based clinical application of H2S in order to achieve the desired outcome. The signaling mechanisms underlying the differential effects of H2S on cell survival are further discussed by Yang. The effects of H2S on cell survival involve a wide array of signaling pathways, such as oxidative stress, cell cycle regulation factors, serine/threonine-selective protein kinases including MAPK and the PI3/Akt pathway, to name a few. Interestingly, many common signaling molecules are activated by H2S, but lead to cell growth arrest in one type of cell and cell growth stimulation in other cell types. The diversity and complexity of H2S effects are further emphasized by Liu et al. with a focus on signaling mechanisms underlying the protective effects of H2S in the kidney. Renal metabolism of H2S is closely linked to renal function. More specifically, H2S appears to recruit some unique signaling pathways in the kidney to regulate renal function. While H2S has no effect on cAMP in other vascular systems, this very gasotransmitter lowers cAMP content in the kidney and induces vasoconstriction in renal circulation. Desai et al. summarize the involvement of H2S in regulating basic metabolic processes. The high production rate of H2S in pancreatic β-cells controls the basal insulin secretion level through its inhibitory effect on pancreatic KATP channels and its proapoptotic effect on β-cells. As an insulin-sensitive tissue, adipose tissue alters its sensitivity to insulin depending on the availability of H2S. Deficiency in CSE expression and endogenous H2S production in the pancreas and adipose tissue is responsible for reduced insulin secretion and insulin resistance, leading to the manifestation of the metabolic syndrome, including obesity, hypertension and diabetes. The reproductive system is also affected by H2S, as reviewed by Zhu and Ni. Endogenous production of H2S in reproductive organs has also been demonstrated. H2S production in male and female reproductive systems probably occurs via both H2S-generating enzymes cystathionine β-synthase and CSE. Human and rat penile tissues, more specifically corpus cavernosum smooth muscles, can be relaxed by endogenous and exogenous H2S, leading to sustained erection. In females, low oxygen levels increase H2S production in human intrauterine tissues. High concentrations of H2S exposure may cause reduced fecundity and increased offspring size in fish. Understanding these unique effects of H2S will pave the way for therapeutic interventions of endocrine and reproductive disorders.
Pathophysiological abnormalities related to altered H2S metabolism and functions are reviewed in the second part of this special issue. Predmore and Lefer provide a critical evaluation on the role of H2S in myocardial protection against ischemia–reperfusion damage as well as the cardioprotective signaling pathways involved. Intentionally exposing the heart to H2S surges preconditions the heart to delay or reduce myocardial infarction. H2S can also protect the heart from the lethal damage of ischemia through a post-conditioning mechanism, which appears to offer a better clinical applicability. As an alternative to ‘staged reperfusion’, the timing of starting H2S post-conditioning after the ischemia but before reperfusion is critical for its protective effect. As H2S production requires either l-cysteine or homocysteine as the substrate, disorders related to these two substrates are naturally related to the H2S level. Lynn and Austin discuss the role of H2S in the complications of hyperhomocysteinemia, especially in the case of atherosclerosis. They extract evidence from the literature to show that H2S is involved in multiple steps in the development of atherosclerosis, including monocyte infiltration and the accumulation of foam cells, endothelial dysfunction and smooth muscle cell proliferation. Increasing the endogenous H2S production or utilization of H2S donors proves to be beneficial for the management of atherosclerosis.
The controversy surrounding the relationship between H2S and inflammation is discussed by Whiteman and Winyard. Both anti-inflammatory and pro-inflammatory effects of H2S have been reported in different animal models and cultured cells. Beyond the concentration ranges, the sources of H2S (endogenously produced versus exogenously applied) and animal species/tissue/cell-type differences, the pace of inflammation development (acute vs chronic) and the rate of H2S delivery all play roles. This leads Whiteman and Winyard to believe that the compounds that slowly release H2S may be better pharmacological tools to mimic physiological fluctuation of endogenous H2S levels and deal with different inflammation disorders.
The last section of this special issue contributes to the appraisals for the development of new H2S-releasing or -delivering compounds. Their clinical pharmacology and potential clinical significance are highlighted. Sparatore et al. describe a new series of H2S-donating hybrids that combine with pharmacologically active compounds and have H2S-releasing capacity. The hybrids are made between H2S and diclofenac, aspirin, sildenafil, latanoprost and levodopa, respectively. These compounds have been tested for their potential in dealing with inflammation, cardiovascular, urologic and neurodegenerative diseases. Some of these leading compounds possess enhanced potencies, tolerance and safety compared with their parent compounds. H2S can also be delivered through organosulfur compounds. As reviewed by Gu and Zhu, Allium vegetables are examples of the sources of organic sulfur-containing compounds. More specifically, diallyl disulfide, diallyl trisulfide and S-ally cysteine are all ingredients of garlic, which generate H2S under different conditions. Other pharmacological approaches to introduce H2S include the synthesis of cysteine analogs and H2S-releasing moieties. The advantages and drawbacks of these compounds, releasing H2S or promoting endogenous H2S production, have been compared and summarized.
Rapid advances in our understanding of the physiological roles of H2S in recent years, coupled with the continued improvement of H2S detection techniques and methodologies, have shed new light on the pathogenesis of many diseases. Although the majority of the studies on pathological roles of H2S were conducted in animal models, some clinical data have been reported, indicating both the involvement of H2S in pathogenic processes and the usefulness of targeting H2S level as a novel therapeutic venue. These exploratory clinical studies merit further confirmation and expansion. A successful translation of basic scientific knowledge to clinical practice requires the participation and collaboration of basic researchers, clinical scientists and the pharmaceutical industry. One of the challenges confronting the H2S research field is the clinical interpretations of and implications for many cellular and molecular effects of H2S, and this uncertainty cannot be alleviated, even by considering the effect of H2S at the whole-animal level. The advantages of the newly emerged H2S-releasing hybrids and organosulfur compounds over their predecessors are multifold, especially with regard to their potency and efficiency in dealing with various diseases. Indeed, the limitations of these new H2S-based compounds have not been fully examined. For example, as H2S often produces opposite functional changes in different tissues or organs, selective administration of H2S-based compounds with controlled release rates should be considered. Nevertheless, with the momentum of the intensified research interest on H2S medicine and the coordinated effort for knowledge translation, a follow-through in clinical practice after breakthroughs in our understanding of the physiological importance of H2S is both feasible and promising, and it certainly will be rewarding.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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