Hydrogen Sulfide Attenuates the Recruitment of CD11b+Gr-1+ Myeloid Cells and Regulates Bax/Bcl-2 Signaling in Myocardial Ischemia Injury
TL;DR: The results demonstrated that the administration of NaHS improved survival, preserved left ventricular function, limited infarct size, and improved H2S levels in cardiac tissue to attenuate the recruitment of CD11b+Gr-1+ myeloid cells and to regulate the Bax/Bcl-2 pathway.
Abstract: Hydrogen sulfide, an endogenous signaling molecule, plays an important role in the physiology and pathophysiology of the cardiovascular system. Using a mouse model of myocardial infarction, we investigated the anti-inflammatory and anti-apoptotic effects of the H2S donor sodium hydrosulfide (NaHS). The results demonstrated that the administration of NaHS improved survival, preserved left ventricular function, limited infarct size, and improved H2S levels in cardiac tissue to attenuate the recruitment of CD11b(+)Gr-1(+) myeloid cells and to regulate the Bax/Bcl-2 pathway. Furthermore, the cardioprotective effects of NaHS were enhanced by inhibiting the migration of CD11b(+)Gr-1(+) myeloid cells from the spleen into the blood and by attenuating post-infarction inflammation. These observations suggest that the novel mechanism underlying the cardioprotective function of H2S is secondary to a combination of attenuation the recruitment of CD11b(+)Gr-1(+) myeloid cells and regulation of the Bax/Bcl-2 apoptotic signaling.
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TL;DR: This review focuses on the recent progress on functional and mechanistic aspects of H2S in the inflammatory and immunoregulatory processes of cardiovascular disorders, importantly myocardial ischemia, heart failure, and atherosclerosis.
Abstract: Hydrogen sulfide (H2S), the third endogenous gaseous signaling molecule alongside nitric oxide (NO) and carbon monoxide, is synthesized by multiple enzymes in cardiovascular system. Similar to other gaseous mediators, H2S has demonstrated a variety of biological activities, including anti-oxidative, anti-apoptotic, pro-angiogenic, vasodilating capacities and endothelial NO synthase modulating activity, and regulates a wide range of pathophysiological processes in cardiovascular disorders. However, the underlying mechanisms by which H2S mediates cardiovascular homeostasis are not fully understood. This review focuses on the recent progress on functional and mechanistic aspects of H2S in the inflammatory and immunoregulatory processes of cardiovascular disorders, importantly myocardial ischemia, heart failure, and atherosclerosis. Moreover, we highlight the challenges for developing H2S-based therapy to modulate the pathological processes in cardiovascular diseases. A better understanding of the immunomodulatory and biochemical functions of H2S might provide new therapeutic strategies for these cardiovascular diseases.
70 citations
Cites background from "Hydrogen Sulfide Attenuates the Rec..."
...In a murine MI model subjected to pre- and post-coronary artery occlusion, exogenous H2S treatment reduced the recruitment of CD11b Gr-1myeloid cells to the myocardium, inhibited their migration from the splenic reservoir, and decreased serum TNF-α and IL-1β levels, thereby protecting against ischemic myocardial injury (Zhang et al., 2014)....
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...…artery occlusion, exogenous H2S treatment reduced the recruitment of CD11b+ Gr-1+myeloid cells to the myocardium, inhibited their migration from the splenic reservoir, and decreased serum TNF-α and IL-1β levels, thereby protecting against ischemic myocardial injury (Zhang et al., 2014)....
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TL;DR: It is concluded that although all the H2S donors tested limited infarct size, the pathways involved were not conserved and cardioprotection exhibited by AP39 could result from a direct inhibitory effect on PTP acting at a site different than CypD.
Abstract: Hydrogen sulfide (H2S) is a signaling molecule with protective effects in the cardiovascular system. To harness the therapeutic potential of H2S, a number of donors have been developed. The present study compares the cardioprotective actions of representative H2S donors from different classes and studies their mechanisms of action in myocardial injury in vitro and in vivo. Exposure of cardiomyocytes to H2O2 led to significant cytotoxicity, which was inhibited by sodium sulfide (Na2S), thiovaline (TV), GYY4137 [morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate], and AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol5yl)phenoxy)decyl) triphenylphospho-nium bromide]. Inhibition of nitric oxide (NO) synthesis prevented the cytoprotective effects of Na2S and TV, but not GYY4137 and AP39, against H2O2-induced cardiomyocyte injury. Mice subjected to left anterior descending coronary ligation were protected from ischemia-reperfusion injury by the H2S donors tested. Inhibition of nitric oxide synthase (NOS) in vivo blocked only the beneficial effect of Na2S. Moreover, Na2S, but not AP39, administration enhanced the phosphorylation of endothelial NOS and vasodilator-associated phosphoprotein. Both Na2S and AP39 reduced infarct size in mice lacking cyclophilin-D (CypD), a modulator of the mitochondrial permeability transition pore (PTP). Nevertheless, only AP39 displayed a direct effect on mitochondria by increasing the mitochondrial Ca2+ retention capacity, which is evidence of decreased propensity to undergo permeability transition. We conclude that although all the H2S donors we tested limited infarct size, the pathways involved were not conserved. Na2S had no direct effects on PTP opening, and its action was nitric oxide dependent. In contrast, the cardioprotection exhibited by AP39 could result from a direct inhibitory effect on PTP acting at a site different than CypD.
69 citations
Cites background from "Hydrogen Sulfide Attenuates the Rec..."
...Several in vivo studies have demonstrated that exogenously administered H2S protects against myocardial infarction (Johansen et al., 2006; Calvert et al., 2009, 2010; Szabó et al., 2011;King et al., 2014; Zhang et al., 2014; Lilyanna et al., 2015)....
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...Several in vivo studies have demonstrated that exogenously administered H2S protects against myocardial infarction (Johansen et al., 2006; Calvert et al., 2009, 2010; Szabó et al., 2011;King et al., 2014; Zhang et al., 2014; Lilyanna et al., 2015)....
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TL;DR: The aim of the present review was to provide a critical analysis of formation and role of reactive species, NO and H2S in mitochondria, with a special emphasis on mechanisms of injury and protection that determine the fate of hearts subjected to I/R.
Abstract: Redox signalling in mitochondria plays an important role in myocardial ischaemia/reperfusion (I/R) injury and in cardioprotection. Reactive oxygen and nitrogen species (ROS/RNS) modify cellular structures and functions by means of covalent changes in proteins including among others S-nitros(yl)ation by nitric oxide (NO) and its derivatives, and S-sulphydration by hydrogen sulphide (H2 S). Many enzymes are involved in the mitochondrial formation and handling of ROS, NO and H2 S under physiological and pathological conditions. In particular, the balance between formation and removal of reactive species is impaired during I/R favouring their accumulation. Therefore, various interventions aimed at decreasing mitochondrial ROS accumulation have been developed and have shown cardioprotective effects in experimental settings. However, ROS, NO and H2 S play also a role in endogenous cardioprotection, as in the case of ischaemic pre-conditioning, so that preventing their increase might hamper self-defence mechanisms. The aim of the present review was to provide a critical analysis of formation and role of reactive species, NO and H2 S in mitochondria, with a special emphasis on mechanisms of injury and protection that determine the fate of hearts subjected to I/R. The elucidation of the signalling pathways of ROS, NO and H2 S is likely to reveal novel molecular targets for cardioprotection that could be modulated by pharmacological agents to prevent I/R injury.
51 citations
TL;DR: A wide array of significant roles of H2S in the physiological regulation of all organ functions emerges from this review.
Abstract: H2S belongs to the class of molecules known as gasotransmitters, which also includes nitric oxide (NO) and carbon monoxide (CO). Three enzymes are recognized as endogenous sources of H2S in various cells and tissues: cystathionine g-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). The current article reviews the regulation of these enzymes as well as the pathways of their enzymatic and non-enzymatic degradation and elimination. The multiple interactions of H2S with other labile endogenous molecules (e.g. NO) and reactive oxygen species are also outlined. The various biological targets and signaling pathways are discussed, with special reference to H2S and oxidative posttranscriptional modification of proteins, the effect of H2S on channels and intracellular second messenger pathways, the regulation of gene transcription and translation and the regulation of cellular bioenergetics and metabolism. The pharmacological and molecular tools currently available to study H2S physiology are also reviewed, including their utility and limitations. In subsequent sections, the role of H2S in the regulation of various physiological and cellular functions is reviewed. The physiological role of H2S in various cell types and organ systems are overviewed. Finally, the role of H2S in the regulation of various organ functions is discussed as well as the characteristic bell-shaped biphasic effects of H2S. In addition, key pathophysiological aspects, debated areas, and future research and translational areas are identified A wide array of significant roles of H2S in the physiological regulation of all organ functions emerges from this review.
45 citations
TL;DR: The data suggest that the slow-releasing H2S donor, GYY4137, preserves cardiac function, attenuates adverse remodeling and may exert post-ischemic cardioprotective effects in part through enhanced early post-ISChemic endogenous natriuretic peptide activation.
43 citations
References
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TL;DR: The origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit are discussed.
Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.
5,811 citations
TL;DR: Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea as discussed by the authors.
Abstract: Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. Ischemia-reperfusion injury is also a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. An imbalance in metabolic supply and demand within the ischemic organ results in profound tissue hypoxia and microvascular dysfunction. Subsequent reperfusion further enhances the activation of innate and adaptive immune responses and cell death programs. Recent advances in understanding the molecular and immunological consequences of ischemia and reperfusion may lead to innovative therapeutic strategies for treating patients with ischemia and reperfusion-associated tissue inflammation and organ dysfunction.
2,368 citations
TL;DR: It is shown that H2S is physiologically generated by cystathionine γ-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H 2S levels in the serum, heart, aorta, and other tissues.
Abstract: Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H2S) is now receiving increasing attention Here we show that H2S is physiologically generated by cystathionine γ-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H2S levels in the serum, heart, aorta, and other tissues Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H2S formation in response to vascular activation These findings provide direct evidence that H2S is a physiologic vasodilator and regulator of blood pressure
2,090 citations
TL;DR: It is shown that bona fide undifferentiated monocytes reside in the spleen and outnumber their equivalents in circulation and identifies splenic monocytes as a resource that the body exploits to regulate inflammation.
Abstract: A current paradigm states that monocytes circulate freely and patrol blood vessels but differentiate irreversibly into dendritic cells (DCs) or macrophages upon tissue entry. Here we show that bona fide undifferentiated monocytes reside in the spleen and outnumber their equivalents in circulation. The reservoir monocytes assemble in clusters in the cords of the subcapsular red pulp and are distinct from macrophages and DCs. In response to ischemic myocardial injury, splenic monocytes increase their motility, exit the spleen en masse, accumulate in injured tissue, and participate in wound healing. These observations uncover a role for the spleen as a site for storage and rapid deployment of monocytes and identify splenic monocytes as a resource that the body exploits to regulate inflammation.
1,946 citations
TL;DR: It is demonstrated that H2S is an important endogenous vasoactive factor and the first identified gaseous opener of KATP channels in vascular SMCs and production from vascular tissues was enhanced by nitric oxide.
Abstract: Hydrogen sulfide (H(2)S) has been traditionally viewed as a toxic gas. It is also, however, endogenously generated from cysteine metabolism. We attempted to assess the physiological role of H(2)S in the regulation of vascular contractility, the modulation of H(2)S production in vascular tissues, and the underlying mechanisms. Intravenous bolus injection of H(2)S transiently decreased blood pressure of rats by 12- 30 mmHg, which was antagonized by prior blockade of K(ATP) channels. H(2)S relaxed rat aortic tissues in vitro in a K(ATP) channel-dependent manner. In isolated vascular smooth muscle cells (SMCs), H(2)S directly increased K(ATP) channel currents and hyperpolarized membrane. The expression of H(2)S-generating enzyme was identified in vascular SMCs, but not in endothelium. The endogenous production of H(2)S from different vascular tissues was also directly measured with the abundant level in the order of tail artery, aorta and mesenteric artery. Most importantly, H(2)S production from vascular tissues was enhanced by nitric oxide. Our results demonstrate that H(2)S is an important endogenous vasoactive factor and the first identified gaseous opener of K(ATP) channels in vascular SMCs.
1,727 citations