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  • Review
  • Open Access

Mechanisms by which hydrogen sulfide attenuates muscle function following ischemia–reperfusion injury: effects on Akt signaling, mitochondrial function, and apoptosis

Journal of Translational Medicine201917:33

https://doi.org/10.1186/s12967-018-1753-7

  • Received: 14 August 2018
  • Accepted: 21 December 2018
  • Published:

Abstract

Ischemia–reperfusion injury is caused by a period of ischemia followed by massive blood flow into a tissue that had experienced restricted blood flow. The severity of the injury is dependent on the time the tissue was restricted from blood flow, becoming more severe after longer ischemia times. This can lead to many complications such as tissue necrosis, cellular apoptosis, inflammation, metabolic and mitochondrial dysfunction, and even organ failure. One of the emerging therapies to combat ischemic reperfusion injury complications is hydrogen sulfide, which is a gasotransmitter that diffuses across cell membranes to exert effects on various signaling pathways regulating cell survival such as Akt, mitochondrial activity, and apoptosis. Although commonly thought of as a toxic gas, low concentrations of hydrogen sulfide have been shown to be beneficial in promoting tissue survival post-ischemia, and modulate a wide variety of cellular responses. This review will detail the mechanisms of hydrogen sulfide in affecting the Akt signaling pathway, mitochondrial function, and apoptosis, particularly in regards to ischemic reperfusion injury in muscle tissue. It will conclude with potential clinical applications of hydrogen sulfide, combinations with other therapies, and perspectives for future studies.

Keywords

  • Hydrogen sulfide
  • Muscle
  • Ischemia reperfusion injury
  • Apoptosis
  • Akt
  • Mitochondria
  • eNOS

Background

Ischemic-reperfusion injury (IR) occurs when there is a restriction of blood flow to tissue, followed by massive reperfusion caused by sudden blood flow to the affected area. Deprived of oxygen cells rely on anaerobic metabolism during IR, resulting in decreases in pH, followed by reduction of available ATP and calcium overload in cells. This is accompanied by opening of the mitochondrial permeability transition pore (mPTP), disrupting mitochondrial membrane potential and electron transport chain [1]. Lack of oxygen can also lead to capillary dysfunction and breakdown of cell membranes, contributing to tissue necrosis [13]. IR can affect many tissues, including brain, intestine, kidney, heart, and skeletal muscle. It is also associated with impaired healing of chronic wounds, organ transplant complications, and tourniquet application [35]. IR can be a result of different types of injuries that include compartment syndrome, crush injuries, and vascular injuries [3]. In addition to loss of blood flow and nutrients to affected tissues IR is exasperated by increased inflammation and reactive oxygen species (ROS) release, which cause further damage to cells and can initiate apoptosis by mPTP opening and caspase activation [3, 6, 7].

Muscle, particularly skeletal muscle, is one of the primary tissues affected by IR, which is marked by changes in microvasculature, muscle volume, loss of function, and increased inflammation [3, 8, 9]. Different tissues have specific critical times before onset of serious injury; for muscle this is approximately 4 h [8]. Beyond this time unrepairable tissue necrosis and tissue loss occurs due to mitochondrial loss and apoptotic activation, which can necessitate amputation of the affected limb [1012]. Different types of muscle display differing response to ischemia based on their mitochondrial content. Highly oxidative muscles such as the soleus displayed less severe damage in response to IR than glycolytic muscles such as the gastrocnemius, likely due to increased anti-oxidant presence in oxidative muscles [9]. Additionally, IR can affect organs beyond the affected limb by increases of inflammatory cytokines. For example, kidney and heart cells are extremely vulnerable to restrictions of blood flow, and introduction of free radical scavengers can improve total body function in ischemic animal models by reduction of inflammatory cytokines such as interleukins (IL) and tumor necrosis factor alpha (TNFα) [1319].

Hydrogen sulfide (H2S) is a gasotransmitter, along with nitric oxide (NO) and carbon monoxide (CO) that initiates a variety of signaling pathways within cells. Hydrogen sulfide has traditionally been thought of as a poisonous gas emitting a rotten egg smell, but recent evidence suggests that in micromolar amounts H2S can alter various signaling pathways involved in vasodilation, metabolism, apoptosis, and mitochondrial electron transport chain (ETC) [2023]. In addition to environmental H2S that is absorbed across cell membranes via diffusion cells are also able to produce small amounts of endogenous H2S by reverse transsulfuration of dietary L-homocysteine [24]. This process is mainly carried out by the cytosolic enzymes cystathionine β-synthase (CBS; mostly found in nerves) and cystathionine γ-lyase (CSE; mostly found in muscle), which utilize cystathione to convert homocysteine to cysteine, with H2S as a by-product [24, 25]. Additionally, H2S can also be generated by mitochondrial mercaptopyruvate sulphur transferase (3-MST), which utilizes mercaptopyruvate to form a persulfide intermediate by cysteine transanimation of α-ketoglutarate and l-cysteine. Presence of a reducing agent such as thioredoxin then releases H2S and pyruvate [25, 26]. Once released from cells H2S has a short half-life of up to 12 min in vivo (in contrast to aerosol half-life of up to 37 h), making continuous endogenous production of H2S critical to its activity [27, 28]. Interestingly, it has been shown that the three major endogenous hydrogen sulfide producing enzymes (CBS, CSE, 3-MST), as well as total hydrogen sulfide are reduced in muscle and kidney following ischemia, which can be attenuated through introduction of H2S donors [2931], suggesting that H2S can be useful in reducing IR complications. Once released H2S can modify proteins by sulfurhydration to augment preservation by cryoprotection, alter ion channel activity (K+, Ca2+, KATP), regulate apoptosis by affecting Akt (also known as protein kinase B) and phosphoinosiol kinase (PI3K)-mammalian target of rapamycin (mTOR), reduce inflammation, act as a free radical scavenger, and alter mitochondrial electron transport chain activity by alteration of KATP pore formation and regulation of cyclic AMP (cAMP) activity [21, 24, 26, 3234]. H2S uses the KATP pump as a second messenger system, and is also proposed to cross-talk with the other gasotransmitters by regulation of endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 to affect the activities of NO and CO, respectively [26, 35]. H2S can be introduced in vivo by both fast release (sodium hydrosulfide: NaHS) and slow release Morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate: (GYY4137), diallyl trisulfide, with differing effects. The fast release donors release their drug in a quick burst which are effective for short-term effects such as immediate modulation of cell metabolism and inflammation reduction, while the slow release donors are more effective at promoting long-term effects on muscle recovery and tissue integrity due to gradual release of H2S [36, 37].

Hydrogen sulfide has been proposed as a therapy to prevent IR damage by reducing free radical induced stress, promoting mitochondrial function, activating vascularization pathways, and reducing apoptosis. Administration of H2S donors have improved survival following myocardial infarct in mice when combined with cardiopulmonary resuscitation [38]. Most research has been focused on the effects of H2S as a therapeutic agent in cardiac ischemia, with little knowledge on its effects in skeletal muscle. This review will cover the effects of H2S in reducing IR mostly in cardiac muscle, with some inferences drawn from studies in other tissues. The primary focus will be on metabolic effects associated with IR injury, primarily Akt-eNOS signaling, mitochondrial ETC and mPTP activity, and cellular apoptosis.

H2S ameliorates detrimental effects of muscle ischemia by altering Akt signaling

Binding of insulin growth factor 1 (IGF-1) to its receptor activates a signaling cascade that activates PI3K to activate downstream Akt and adenosine monophosphate kinase (AMPK) [33, 39, 40]. Akt functions in muscle synthesis by promoting protein synthesis by activating mammalian target of rapamycin (mTOR), and preventing degradation by inactivating forkhead box (FoxO) gene transcription [33, 40]. One possible mechanism of preventing muscle damage following IR is to activate Akt to promote mTOR activation by phosphorylation of Akt at Ser473 and Thr308. One study showed that hearts isolated from rats pretreated with 50 µM NaHS prior to IR displayed increased Akt and mTOR phosphorylation, along with decreased cell death and improved coronary flow [33]. This same study also showed that H9c2 cardiomyocyte cells treated with the mTOR inhibitor PP242 prevented NAHS induced mTOR phosphorylation and cardioprotection [33]. Timing and dosage of NaHS are also critical, as 100 µM NaHS decreased heart function, and administration following reperfusion did not result in increased mTOR phosphorylation in isolated heart tissue [33]. A report which pretreated H9c2 cells with 100 µM NaHS for 30 min prior to inducing cardiotoxicity with 5 µM doxorubicin, and found that NaHS pretreatment increased Akt and FoxO3a phosphorylation, which was decreased by doxorubicin alone [32]. The action of H2S was augmented by the free radical scavenger N-acetyl-l-cysteine (NAC). Disruption of Akt activity by the inhibitor LY294002 prevented Akt anti-apoptotic activity, and resulted in increased nuclear localization of FoxO3a [32], demonstrating that Akt activity is indispensable for H2S protection of cardiomyocytes against cell death. Additionally, mTOR complex 2 can promote Akt1 phosphorylation, which promotes cardioprotection that is ablated by the mTOR inhibitor PP242, even in the presence of exogenous 50 µM NaHS [33]. H2S can also exert cardioprotective functions when administered post-ischemia. Yong et al. [41] performed a study measuring cardiac function and metabolic activation following 100 µM NaHS administered post-myocardial infarct in either six-ten second administrations or a single 2 min administration. It was observed that NaHS administration, particularly in the six-ten second intervals, resulted in reduced infarct size, with increased phosphorylation of Akt and protein kinase C [41]. Blockage of Akt or PKC with 15 µM LY294002 or 10 µM chelerythrine resulted in reduced NaHS induced cardioprotection in the 2 min continuous administration model [41], suggesting that timing of H2S donor administration can activate different pathways. These data suggest that the Akt-mTOR pathway is a critical regulator of muscle function and survival in ischemia, and the absence of either is detrimental to muscular function. The protective effects of Akt activation by H2S are not limited to muscle; it has been demonstrated that an increase in Akt phosphorylation by NaHS pretreatment in hepatic IR, which was abolished by inhibiting Akt with LY294002 [42], suggesting that Akt is a pathway that can be targeted in many tissues affected by IR. Taken together, this data suggests that activation of the Akt pathway can reduce ischemia in various organs by attenuating mTOR induced cell proliferation, and Akt activity is essential for H2S activity in all tissues.

Effects of H2S and Akt on vascularization

Akt also crosstalks with NO signaling pathways to promote vascularization through vascular endothelial growth factor (VEGF) activation [35, 43]. Deficiencies of either H2S or NO levels have been linked with increased risk of cerebral IR by vascular restriction [44]. VEGF is a potent pro-angiogenic factor that promotes vascularization in ischemia and cancer through a variety of signaling pathways such as Akt and STAT3 [32, 40, 45, 46]. In ischemic muscle addition of VEGF can result in reduced damage and improved function. Rats subjected to hind limb ischemia induced by unilateral external iliac and femoral artery and vein ligation, then injected with an alginate gel containing 3 µg of VEGF and/or IGF-1 demonstrated that either treatment resulted in improved vascularization measured by laser Doppler perfusion injury, reduced fibrosis, and improved muscle regeneration and function [47]. VEGF and IGF-1 acted in synergy to improve ischemia response superior to either treatment alone [47]. Administration of H2S donor once or twice a day using a dose of .25–.05 mg/kg over 7 days resulted in increased blood flow to rat hind limbs following femoral artery ligation [48]. Another study involved implanting muscle derived stem cells into mice with muscular dystrophy [49]. It was found that while stem cells alone stimulated in vivo angiogenesis and muscle regeneration, responses were improved when the cells were transduced to overexpress VEGF. Cells expressing soluble forms-like tyrosine kinase-1 displayed significantly less vascularization and increased fibrosis [49], demonstrating that VEGF is crucial to re-establishment of vascularization following IR. In addition to blood flow, VEGF also promotes innervation of damaged muscles. Introduction of VEGF containing gel into damaged human sternomastoid displayed 50 percent innervated motorend plates, compared to only 5 percent for blank gels [47, 50]. VEGF administration also increased expression of nerve growth factor and glial-derived neurotrophic factor, improving axonal regeneration in damaged muscle. Inhibition of the nerve growth factors disrupted VEGF induced nerve repair [50], showing that VEGF acts on a variety of vascular, neural, and cell growth signaling pathways to repair muscular damage and restore function. VEGF activity is augmented by eNOS, and VEGF also acts to upregulate eNOS expression in endothelial cells, forming a feedback loop [51, 52]. Akt is involved in the eNOS-VEGF signaling pathway as an upstream regulator, and has been implicated in regulation of vascularization in many ischemic tissues [35, 51, 53]. One experiment induced hind limb ischemia in rats by femoral artery ligation, followed by daily intraperitoneal NaHS injection (50 µmol/kg). It was found that Akt, VEGF, and VEGF receptor 2 activity all increased in endothelial cells near the ligation site, along with increased measured vascular flow [54], demonstrating a role for Akt in VEGF induction. The study by Yong et al. showed that the 10 s administrations of NaHS resulted in increased expression of eNOS, suggesting that eNOS was critical to NaHS induction of angiogenesis [41]. H2S administration reduced cardiac failure induced by transverse aortic constriction by upregulation of eNOS that was dependent on CSE activity, as CSE knockout mice did not respond to H2S donor administration [55]. A similar study found that a large dose (100 µg/kg) of Na2S restored eNOS activity in CSE knockout mice, but mice lacking phospho eNOS activity were unresponsive to H2S donor treatment following IR [56]. eNOS is critical to angiogenesis during ischemia, as eNOS knockout resulted in absence of vascularization following NaHS administration [35]. Dietary H2S sources can also induce Akt and eNOS induced vascularization, as demonstrated by a study done injecting mice with daillyl trisulfide, a component of garlic oil that contains H2S. A daily injection of 500 µg/kg daillyl trisulfide over 10 days resulted in improved blood flow following hind limb ischemia, along with increased Akt and eNOS phosphorylation. Akt and eNOS knockout mice were not affected by the treatment, demonstrating that both are essential to vascular repair in IR [57]. It has been shown that dietary and environmental sources (ozone, garlic, vitamin E) have been effective in promoting IR healing through free radical scavenging, and likely also vascular signaling [13, 16, 20, 5759]. The effects of H2S in improving IR response through Akt-eNOS are not limited to muscle, as demonstrated by use of H2S donors to improve angiogenesis following ischemia in intestine [35] and brain [53], suggesting a wide range of targets for H2S directed therapies.

In addition to affecting vascularization through VEGF and eNOS, H2S can also directly interact with NO to produce nitroxyl, which has a longer half-life than either NO or H2S. Both H2S and NO presence are neccesary to produce nitroxyl, and they work synergestically to promote smooth muscle relaxation and portal vein vasodilation [60]. Low nitroxyl concentrations have been shown to be beneficial to vasodilation, cardiac function, smooth muscle relaxation, and cGMP activity, although high levels can be neurotoxic and inflammatory [60, 61]. More research is necessary to deduce the exact roles of H2S and NO crosstalk on VEGF activity and vascularization in order to safely induce vascularization while avoiding adverse side effects.

Summary of the effects of H2S on Akt activity and IR

The mechanism of H2S to regulate Akt pathways is shown in Fig. 1. H2S activates PI3 K, which then phosphorylates Akt. Once activated Akt can activate eNOS, which is upregulated by VEGF and VEGF receptor. VEGF also functions synergistically with eNOS to promote vascular function, which is disrupted if either eNOS or Akt is blocked. Akt activates the mTOR complex to promote protein synthesis and cell growth. Akt also phosphorylates FoxO3 to prevent its translocation to the nucleus, preventing autophagy via Beclin 1 and protein degradation via activation of the ubiquitin proteosome pathway by MuRF1 [62]. Akt can also be activated by mTOR complex 2 to augment its activity [33]. Akt is a pluripotent signaling regulator that regulates many pathways that regulate cell survival and angiogenesis, making it a prime target for IR therapeutic strategies.
Fig. 1
Fig. 1

Roles of H2S in modulating Akt signaling pathways involved in ischemia reperfusion injury and recovery. H2S activates PI3 K and downstream Akt phosphorylation, which can also be activated by mTORC2. Akt can subsequently activate mTORC1 to regulate protein synthesis and cell proliferation, eNOS to activate vascularization by VEGF, and induce phosphorylation of FoxO3 to prevent activation of genes promoting autophagy and ubiquitination

Mitochondrial electron transport chain function

The mitochondrial electron transport chain (ETC) is comprised of 5 subunits that utilize the electron carriers nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) to ultimately drive ATP production via a proton gradient. Electrons flow through the ETC along the five complexes embedded in the mitochondrial inner membrane. Complex I oxidizes NADH and reduces coenzyme Q. Succinate is oxidized by complex II, which also reduces CoQ. Complex III oxidizes coenzyme Q and reduces cytochrome C that donates an electron to complex IV, reducing oxygen to water. Complex V couples proton flow from the outer to the inner membrane with an electrochemical gradient to drive the complex to phosphorylate ADP. The activity of complex V is regulated by ADP levels; in low activity states the rate of ATP hydrolysis is reduced, resulting in less available ADP to be phosphorylated by complex V [63]. Respiration uncoupling occurs in pathologic states due to damage to the inner membrane or to complex V, resulting in loss of ADP regulation, impaired energy production, and increased mitochondrial permeability [63].

Effects of mitochondrial ETC dysfunction in IR

During IR there is an alteration of metabolic pathways such as AMPK, which is a regulator of mitochondrial activity through activation of liver kinase B1. AMPK can be activated by stress associated with IR, leading to decreases in available cellular ATP [15, 64]. One of the major features of IR is a shift towards anaerobic metabolism, as demonstrated by decreases in blood glucose and increases in lactate, glycerol, and pyruvate measured by microdialysis in the early stages of reperfusion [5, 65]. During ischemia lack of available oxygen results in increased pyruvate and cellular acidification. Cells attempt to remove the excess acid by use of the Na+/H+ and Na+/Ca2+ pumps, which leads to increased cytosolic Ca2+ levels. The inhibition of Ca2+ transport by low ATPase activity is a result of decreased ATP production by the oxygen dependent electron transport chain [66]. Acidic cellular pH and NADH accumulation keep the mPTP closed during ischemia, but during reperfusion the rapid resumption of oxidative phosphorylation and restoration of normal cytosolic pH results in mitochondrial Ca2+ uptake, which opens the mPTP, resulting in free radical release and cell death [66, 67]. Surviving cells are affected by ROS, which cause mitochondrial proton leak and uncoupling of the electron transport chain from ATP pump activity, exasperating the available ATP crisis seen in IR. There is conflicting evidence on the extent of mitochondrial dysfunction in IR. One study showed that a 1 h tourniquet application did not result in significant changes in citrate synthase or mitochondrial complex I-III activities [11]. However another study showed that while a 25 min cardiac ischemia followed by 3 min of reperfusion did not change mitochondrial complex enzymatic activity, it did result in complex I thiol modifications and increased ROS production [68], suggesting that even short IR results in increases in oxidative stress within mitochondria. It has been shown that cardiac IR resulted in decreased complex III activity, lipid peroxidation, and hydrogen peroxide production, which were attenuated by hypoxic but not normoxic reperfusion [7], so the rapid introduction of oxygen following ischemia results in superoxide and free radical production that result in tissue damage and mitochondrial dysfunction. A more severe ischemic injury, such as dual hind limb artery ligation mimicking peripheral artery disease resulted in decreased respiration across mitochondrial complexes I, III, and IV, along with increased magnesium superoxide dismutase (MnSOD) expression [69], suggesting that the length and severity of the IR is a major factor in preserving mitochondrial oxidative function. It is imperative to find therapeutic methods to reduce the severity of mitochondrial damage in IR, which has been linked with detrimental outcomes in ischemic stroke due to alterations in mitochondrial metabolic intermediates such as NADH and acetyl CoA, along with mPTP associated stress [70].

H2S mediated attenuation of IR induced mPTP activation

Hydrogen sulfide has been implicated in protection against myocardial infarction by modulation of mitochondrial activity, particularly in regulating the mPTP. Activation of the KATP channel by protein kinase C inhibits opening of the mPTP, which prevents ROS release and cell death [71]. Treating cardiomyocytes with NaHS resulted in increased PKC translocation to the cell membrane, increased mitochondrial membrane potential, and elevated KATP channel activation, resulting in decreased mitochondrial cytochrome C release, less mPTP activation, and improved cardiomyocyte survival [72]. H9c2 cardiac cells treated with 400 µM NaHS and the KATP channel openers diazoxide or pinacidil were protected from high glucose induced stress by increasing KATP activity and reducing oxidative stress [73]. Inhibition of mPTP and cytochrome C release by NaHS treatment has also been observed in rat lungs subjected to acute lung injury, along with reduced mitochondrial swelling and improved lung pathology [74]. Seven day administration of NaHS (5.6 mg/kg/day) in a mouse model of Parkinson’s disease resulted in decreased neuronal cell death and increased KATP channel activity [75]. It has even been demonstrated that inhaled H2S had neuroprotective effects in mice exposed to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce neural damage [76]. The mechanism by which H2S affects KATP activity is under debate. The KATP channel is a heterooctomeric complex that is encoded by the Kir6.1 and Kir6.2 genes that encode the pore forming subunits, and the sulfonylurea receptor (SUR)1 and SUR2 regulatory subunits [71]. The genes for Kir6.1 and SUR2 are next to each other on chromosome 12p12.1, as are Kir6.2 and SUR1 on chromosome 11p15.1, suggesting that the subunits are under similar regulatory control [77, 78]. In muscle the Kir6.1 and SUR2 subunits are predominately expressed [71]. Colonic smooth muscle cells treated with 1 mM NaHS displayed increased KATP activity and SUR2 but not Kir6.1 sulfhydration [79], suggesting that H2S can increase expression or at least activity of KATP pore subunits. One report showed that rats exposed to inhaled tobacco smoke displayed lower levels of serum H2S, and reduced gene expression of CSE and SUR2 in aortic smooth muscle, inhibiting both endogenous H2S levels and action [80]. However another study observed that NaHS protected against neuronal damage in both wild type and Kir6.2 knockout mice, and that uncoupling protein (UCP) 2 knockout mice were not affected by NaHS administration, leading to the suggestion that H2S activity was dependent on the presence of UCP-2, not KATP pore subunits [75]. More research needs to be done to determine the effects of H2S on KATP pore subunit expression in ischemic muscle.

H2S alteration of mitochondrial cAMP activity

H2S also affects mitochondrial activity through modulation of cyclic AMP (cAMP) activity. cAMP is a second messenger that can exert many effects on muscles, including stimulating glucose transport and activating protein kinase A to stimulate mitochondrial electron transport chain activity [8183]. It has been shown that livers from rats treated with 10 µM NaHS displayed increased cAMP activity and PKA expression [21]. cAMP is inhibited in the mitochondria by phosphodiesterase 2A (PDE2A), which was inhibited by exogenous NaHS, resulting in increased mitochondrial PKA and electron transport chain activity [21]. This activity has not yet been observed in ischemic muscles, but research into the effects of H2S on mitochondrial cAMP-PDE2A activity could determine if H2S exerts ubiquitous or cell type specific effects on mitochondrial electron transport chain regulation. Since it has been shown that the presence of exogenous H2S stimulates production of the three endogenous H2S producing enzymes (CBS, CSE, 3-MST) [29], it is possible that H2S treatment could alter mitochondrial activity by increasing endogenous production, and affecting downstream mitochondrial function by increasing activity of the KATP channel and/or cAMP signaling. These pathways potentially regulating the effects of H2S on mitochondrial activity in muscle are illustrated in Fig. 2. IR can inhibit endogenous H2S production by CSE, which results in downregulation of KATP pore subunits and UCP-2. It also prevents ETC stimulation as a result of cAMP inhibition by PDE2A. These effects can be reversed by introduction of exogenous H2S, making H2S an attractive candidate for attenuating mitochondrial induced cell death by reducing mPTP opening.
Fig. 2
Fig. 2

Restortion of mitochondrial ATP synthesis pathways by ischemia and H2S in muscle. Dietary L-homocysteine undergoes a reverse transsulfuration reaction by CBS, CSE, and 3-MST to produce endogenous H2S. Ischemia reduces expression of these enzymes, resulting in decreased endogenous H2S production. Introduction of an exogenous H2S donor (NaHS) can increase expression of the enzymes, resulting in increased endogenous H2S synthesis. This affects mitochondria by increasing KATP activity through increased gene expression of SUR2A-Kir6.1 and/or acting through UCP-2. This leads to increased Ca2+ export form the mitochondria, stimulating ATP transport. H2S also upregulates cAMP by inhibiting PDE2A, resulting in increased mitochondrial PKA activity to stimulate the electron transport chain (ETC), resulting in increased oxygen utilization and ATP production

H2S and complex IV inhibition

Hydrogen sulfide also acts as a reversible inhibitor of mitochondrial complex IV, the terminal complex in the ETC, thus reducing mitochondrial oxidative phosphorylation [84]. H2S has been associated with reduced metabolism by inducing a hibernation like state. Blackstone et al. demonstrated that rats exposed to 80 ppm of inhaled H2S for 6 h displayed less oxygen utilization with lower core body temperature and carbon dioxide output [85]. The rats returned to a normal metabolic state after being returned to room air, suggesting that H2S induced hypometabolic state is easily reversible and produces no long term detrimental effects [84, 85], thus potentially reducing trauma following injury by lowering mitochondrial metabolic function. Upon return to normal conditions the rats displayed no behavioral detriments that have been associated with long term hydrogen sulfide exposure [85]. Several studies have shown that inhaled hydrogen sulfide up to 100 ppm for 30 min rapidly induces a hypometabolic state that reduces inflammation, apoptosis, and tissue function in IR models of renal and lung damage and hypoxia by reducing oxidative stress and mitochondrial oxygen utilization [8688]. Interestingly, H2S and cryopreservation been used to preserve kidneys for successful transplantations while avoiding IR associated tissue damage that is not attenuated by cryopreservation alone [89]. To date there has been no work done on H2S induced preservation of skeletal muscle following IR, opening up an interesting possibility for future investigation.

H2S reduces ischemic necrosis by reducing cellular apoptosis

Hydrogen sulfide has been widely implicated in the prevention of cellular apoptosis under ischemic conditions. One of the major pathways implicated is the PI3 K-Akt signaling pathway. In addition to stimulating mTOR as described previously, Akt has also been implicated in preventing cell death by activating c-Jun-N-terminal kinase (JNK). Rat cardiomyocytes treated with NaHS or the JNK inhibitor SP600125 displayed inhibited phosphorylation of JNK, which led to decreased cytochrome C release, an increase in B-cell lymphoma (Bcl)-2 expression, and increased cell survival [90]. The timing of NaHS treatment was critical, as administration 1 h following reperfusion did not prevent cellular apoptosis [90]. NaHS has been shown to protect primary human umbilical vein endothelial cells from high glucose induced stress by deactivating Bax through upregulation of Bcl-2, deactivated downstream caspase 3, and upregulated superoxide dismutase, reducing apoptosis by 41 percent compared to untreated cells [91]. Akt activation has also been implicated in protecting hippocampal neurons from IR stress by activating glycogen synthase kinase (GSK)3β and glutamate NMDA receptor subunit epsilon (NR)2A and B [92]. The Akt-NR2 pathway in cerebral IR is augmented by heat shock protein (HSP) 70, as induction of Akt by inhaled H2S also activates HSP70 to prevent cerebral IR induced neural apoptosis, resulting in increased cognitive function measured by Morris maze test [93]. Retinal ganglion cells from rats treated with inhaled H2S prior to retinal IR displayed less apoptosis via regulation of JNK, HSP-90, and caspase-3 [94], suggesting a wide variety of IR types that can be attenuated with H2S treatment. Another study also demonstrated that inhaled H2S prevented neuronal apoptosis induced by MPTP by upregulation of antioxidant genes [76]. GSK3β activation through Akt has also been implicated in protecting cardiomyocytes from apoptosis by preventing mPTP opening and Bax translocation [95]. The connection between ROS, inflammation, and apoptosis in IR is well established [2, 30, 34, 96100]. The inflammatory cytokines TNFα and IL-6 are increased in hepatic reperfusion, which can be attenuated by 5 µM NaHS treatment, along with increased Bcl-2 and decreased Bax and JNK activation [99]. Autophagy was also affected, as Beclin-1 and microtubule-associated protein 1A/1B-light chain 3 (LC3) were decreased by NaHS, resulting in improved hepatic structure and decreased autophagasome detection [99]. Two independent studies found that mouse hepatocytes treated with NaHS displayed increased Akt and GSK3β phosphorylation, correlating with decreased Beclin-1 and LC3 [42, 101], suggesting an Akt-JNK-GSK3-Bcl-2-mPTP pathway activated by IR that is modulated by NaHS in preventing apoptosis and autophagy. This pathway might be augmented by HSP70 and 90, which can encode genes involved in ROS scavenging and antioxidants such as thioredoxin-1, and downregulation of inflammatory TNFα, IL-6, and NF-κB signaling [24, 34, 46, 102104]. Other studies have determined that H2S reduces inflammatory cytokine levels in many cell and tissue types, particularly TNFα and IL-6, suggesting a potent anti-apoptotic function for H2S by deactivating inflammation induced Bax signaling and subsequent mPTP opening, which prevents against further cell damage [18, 19, 105, 106]. For example one study identified that NaHS prevented IL-6 secretion from PC12 neural cells subjected to hypoxic and glucose deprivation stress, allowing for protection against many sources of inflammation that are induced by IR [107]. H2S appears to be multifunctional in affecting many pro-apoptotic pathways associated with increased IR damage, making it an attractive candidate for reducing IR associated cell death and tissue necrosis.

H2S reduction of stress induced apoptosis

As previously mentioned, H2S can attenuate inflammatory cytokines and ROS associated with IR. A few studies have determined that H2S also protects skeletal muscle from IR induced apoptosis by reducing stress and inflammation. Henderson et al. [108] performed a study delivering 10 µM NaHS 20 min prior to 3 h of tourniquet induced hind limb ischemia, followed by 3 h of reperfusion, and found that H2S treated mice showed a reduced apoptotic index of up to 91 percent, which persisted even 4 weeks following the initial injury, along with decreased muscle pathology and cellular apoptosis [108]. The same group also found that myotubes subjected to hypoxia for up to 5 h displayed up to 75 percent less apoptosis when treated with 1–100 µM NaHS, suggesting that H2S could be used to increase the time until critical ischemia begins [109]. There was no significant difference between apoptotic indexes using 1, 10, or 100 µM NaHS, suggesting that even low NaHS doses prevent hypoxia induced apoptosis [109]. The same study also demonstrated that mice treated with 10 µM NaHS prior to IR displayed less muscle pathology and apoptosis detected by TUNEL assay. The time of NaHS administration was critical, as only the mice treated with NaHS 20 min prior to reperfusion displayed less muscle pathology and apoptotic index. There were no significant differences in mice treated with NaHS 1 min prior to reperfusion [109], indicating that in spite of a short in vivo half-life H2S requires little time to act on target tissues. Indeed, it has been suggested that that H2S administration 1 h prior to reperfusion results in superior protection against IR and increased inhibition of JNK and NF-κB activation in kidney [110]. It has also been shown that IR increases mitochondrial superoxide and mPTP opening, leading to skeletal muscle apoptosis [111, 112]. It is plausible that as a free radical scavenger H2S can prevent apoptosis by preventing stress induced mPTP opening, in addition to the previously described activation of PKC [113]. Further work is needed to deduce the exact mechanisms of H2S in reducing IR associated stress.

H2S and microRNAs associated with IR

In addition to activating Akt and inhibiting inflammation, H2S has been implicated in preventing apoptosis by attenuating microRNAs (miRNA): small endogenous non-protein coding RNA strands that act to regulate specific gene expression post-transcriptionally. Kang et al. [114]. pre-treated neonatal rat cardiomyocytes with 30 µM NaHS for 30 min prior to subjecting the cells to hypoxia for 24 h, followed by 2 h of normoxia. Along with increased Bcl-2 expression, and reduced apoptosis and lactate dehydrogenase (LDH) release following NaHS treatment, they also observed that IR increased expression of miRNA-1 (an inhibitor of Bcl-2) in cardiomycoytes, which was reduced by NaHS [114]. Mice subjected to peritonitis by injection of zymosan A that the H2S donor sodium sulfate (Na2S) reduced cardiac inflammation, apoptosis, and necrosis, and reduced myocardial infarct size by 63 percent, which correlated with increased presence of cardioprotective miRNA-21 [115]. Cells treated with the miRNA inhibitor antagomiR-21 did not display reduced inflammation and apoptosis when treated with Na2S, nor did miRNA-21 knockout mice [115], indicating that miRNA-21 is critical for regulating the anti-apoptotic effects of H2S. At least in cardiomyocytes, it appears that H2S reduces inhibitory miRNA-1 and induces miRNA-21, indicating that both pro-and anti-apoptotic miRNAs are potential targets for H2S. It is currently unknown if these or other miRNAs are affected in other muscle types. miRNAs are also implicated in apoptosis in non-muscle tissue that are H2S responsive. GYY4137 reduced TNFα induced apoptosis in spinal cord neurons by enhancing expression of miRNA-485-5p [116], suggesting that a variety of miRNAs involved in stress signaling an cell death can be modulated by H2S. We are likely only beginning to understand the extent of transcriptional regulation of genes by H2S and other gasotransmitters.

Many of the apoptotic regulators affected by H2S, and the cell types they have been identified in, are summarized in Table 1. H2S can regulate apoptosis in many cell types by regulating the Akt-JNK-Bcl-2 pathway, inhibiting mPTP opening, preserving mitochondrial integrity, reducing inflammation, and affecting miRNA expression. It remains to be deduced if these mechanisms are cell type specific, or ubiquitous across many IR types. Future research will identify other anti-apoptotic targets for H2S, and their roles in attenuation of IR in various tissues.
Table 1

Apoptotic regulators associated with ischemic-reperfusion injury that are responsive to hydrogen sulfide

H2S target

Cell/tissue type

Functions

References

Akt

Cardiac, renal, neural, hepatic

JNK, mTOR, GSK3β, NR2A and B activation

[32, 42, 93, 101, 117]

HSP

Retinal, hepatic

Thioredoxin-1 activation, ROS scavenging, reducing inflammatory cytokine induction

[93, 94, 102]

JNK

Cardiac, retinal, renal, hepatic, epithelial

Bcl-2 inactivation, cytochrome C release

[90, 94, 118, 119]

Beclin-1

Cardiac, hepatic

Decrease autophagosome formation

[39, 99]

GSK3β

Cardiac, hepatic, neural

Activate Bax, decrease LC3 and Beclin-1, inhibit mPTP opening,

[6, 72, 95, 101]

Bcl-2

Cardiac, renal, hepatic, neural, epithelial

Prevent cytochrome C release, inactivate Bax

[72, 91, 95, 99, 101, 102, 105]

TNFα, IL-6, IL-1β

Cardiac, skeletal muscle, lung

ROS increase, mPTP opening, Bax activation

[24, 99, 106109, 118]

miRNA (1, 21, 485-5p)

Cardiac, neural

Reduce LDH, regulate transcriptional activation, reduce TNFα activity

[114116]

Clinical administration of H2S in IR

Despite the extensive research that has been conducted using H2S on rodent studies, to date there have been no human studies testing the efficacy of H2S donors on reducing IR. H2S can be released by fast or slow donors. NaHS is a fast release donor of H2S that exerts quick systemic effects. There is some evidence that slow release H2S donors such as diallyl trisulfide (DATS) and GYY4137 might exert longer lasting effects on Akt, eNOS, and prevention of cardiac ischemia [37, 43, 120]. This action might be further improved by combining slow release donors with nanoparticles that aid delivery have greater efficacy than donor alone, such as in using DATS combined with mesporous silica nanoparticles to enhance delivery of H2S to IR affected cardiomyocytes [37]. Patients experiencing IR that are able to quickly get to medical facilities might benefit from low doses of inhaled H2S can induce a hypometabolic state that limits tissue oxygen utilization and prevents further organ damage [86, 87]. Although hydrogen sulfide in air has a longer half-life than in solution (up to 3 days), care must be taken when administering gaseous hydrogen sulfide, and this method is not practical for immediate application of H2S in acute injury. Injectable hydrogen sulfide, likely using slow release donors, will be necessary for these applications. However, since H2S has a short half-life in vivo and solutions (about 12 min), it will be necessary to quickly prepare and administer donors. Tissue specific targeting of H2S is needed to prevent the compound from altering function in undamaged tissue, and travel only to affected targets such as IR affected muscle. It might also be beneficial to use drugs that increase levels of endogenous H2S synthesis by increasing activities of the three main H2S producing enzymes (CBS, CSE, 3-MST). To our knowledge there are not yet any drugs that would increase endogenous expression of these enzymes, although ingestion of foods high in H2S such as garlic might result in increased endogenous levels [121]. Future research is needed to develop methods to efficiently deliver H2S to target tissues while taking care to avoid overdosing patients, which can lead to hydrogen sulfide poisoning and associated complications.

Conclusions and future perspectives

H2S has been demonstrated in many studies to improve response to IR by affecting various signaling pathways involved in metabolic signaling (particularly Akt), mitochondrial integrity and ETC activity, apoptosis, and cell survival in many tissue types. The nature of the H2S donor might be important for determining its effectiveness. Several studies have shown that the slow release donors such as GYY4137 and diallyl trisulfide that dissolve slower in solution may be more effective in reducing apoptosis and inflammation than fast release donors such as NaHS [37, 106, 119]. It has been suggested that H2S might work best when combined with other therapies. A widely used therapy for limb and organ transplantation is hypothermia, which can cause damage to the tissues. Several studies have shown that a combination of H2S and mild hypothermia can prevent IR and limb infection following severe injury, along with extending organ life and reducing tissue metabolic activity when used in transplants [14, 89, 92, 122126]. The major effect of combination therapy is likely ROS scavenging, as therapies with other ROS scavengers such as ozone have proven effective in reducing skeletal muscle IR when combined with hypothermia [16]. Further mechanisms that are involved in H2S-hypothermia limb and organ preservation, such as metabolic pathway regulation, should be deduced in future studies.

In conclusion H2S is a multifaceted regulator of cell signaling that acts on many pathways and tissue types affected by IR. Future research will determine further regulatory mechanisms affected by this gasotransmitter, its effects on post-transcriptional regulation in different cell types, the effectiveness of combined therapies to reduce IR complications, and the possibility of using H2S to extend the critical ischemic time prior to reperfusion in order to allow better treatment of limb and tissue damage in severe injuries.

Abbreviations

3-MST: 

mercaptopyruvate sulphur transferase

AMPK: 

adenosine monophosphate kinase

Bcl: 

B cell lymphoma

cAMP: 

cyclic AMP

CBS: 

cystathionine β-synthase

CO: 

carbon monoxide

CSE: 

cystathionine γ-lyase

eNOS: 

endothelial nitric oxide synthase

ETC: 

electron transport chain

FADH2

flavin adenine dinucleotide

FoxO: 

forkhead box

GSK: 

glycogen synthase kinase

GYY4137: 

Morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate

HSP: 

heat shock protein

IGF: 

insulin growth factor

IL: 

interleukin

IR: 

ischemia-reperfusion injury

H2S: 

hydrogen sulfide

JNK: 

c-Jun-N-terminal kinase

LC3: 

microtubule-associated protein 1A/1B-light chain 3

LDH: 

lactate dehydrogenase

miRNA: 

micro RNA

MnSOD: 

magnesium superoxide dismutase

mPTP: 

mitochondrial permeability transition pore

MPTP: 

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

mTOR: 

mammalian target of rapamycin

Na2S: 

sodium sulfate

NADH: 

nicotinamide adenine dinucleotide

NAC: 

N-acetyl-l-cysteine

NaHS: 

sodium hydrosulfate

NO: 

nitric oxide

NR: 

glutamate NMDA receptor subunit epsilon

PDE2A: 

phosphodiesterase 2A

PI3 K: 

phosphoinositol-3 kinase

ROS: 

reactive oxygen species

SUR: 

sulfonylurea receptor

TNFα: 

tumor necrosis factor α

UCP: 

uncoupling protein

VEGF: 

vascular endothelial growth factor

Declarations

Authors’ contributions

MDW performed literature searches and wrote the manuscript, JCW assisted with literature searches and critically analyzed the manuscript. Both authors read and approved the final manuscript.

Acknowledgements

We thank Patrick B. Collins for reviewing the manuscript.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Not applicable.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Funding

This work was supported in part by an appointment to the Postgraduate Research Participation Program at the U.S. Army Institute of Surgical Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and USAMRMC.

Publisher’s Note

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Authors’ Affiliations

(1)
US Army Institute of Surgical Research, Extremity Trauma and Regenerative Medicine, 3698 Chambers Pass BLDG 3611, Ft. Sam Houston, San Antonio, TX 78234, USA

References

  1. Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell Biology of ischemia/reperfusion Injury. Int Rev Cell Mol Biol. 2012;298:229–317.PubMedPubMed CentralView ArticleGoogle Scholar
  2. Cheng F, Zhang Q, Yan FF, Wan JF, Lin CS. Lutein protects against ischemia/reperfusion injury in rat skeletal muscle by modulating oxidative stress and inflammation. Immunopharmacol Immunotoxicol. 2015;37:329–34.PubMedView ArticleGoogle Scholar
  3. Gillani S, Cao J, Suzuki T, Hak DJ. The effect of ischemia reperfusion injury on skeletal muscle. Injury. 2012;43:670–5.PubMedView ArticleGoogle Scholar
  4. Chen XK, Rathbone CR, Walters TJ. Treatment of tourniquet-induced ischemia reperfusion injury with muscle progenitor cells. J Surg Res. 2011;170:e65–73.PubMedView ArticleGoogle Scholar
  5. Ejaz A, Laursen AC, Kappel A, Jakobsen T, Nielsen PT, Rasmussen S. Tourniquet induced ischemia and changes in metabolism during TKA: a randomized study using microdialysis. BMC Musculoskelet Disord. 2015;16:326.PubMedPubMed CentralView ArticleGoogle Scholar
  6. Li H, Wang Y, Wei C, Bai S, Zhao Y, Wu B, Wang R, Wu L, Xu C. Mediation of exogenous hydrogen sulfide in recovery of ischemic post-conditioning-induced cardioprotection via down-regulating oxidative stress and up-regulating PI3K/Akt/GSK-3β pathway in isolated aging rat hearts. Cell Biosci. 2015;5:11.PubMedPubMed CentralView ArticleGoogle Scholar
  7. Petrosillo G, Di Venosa N, Ruggiero FM, Pistolese M, D’Agostino D, Tiravanti E, Fiore T, Paradies G. Mitochondrial dysfunction associated with cardiac ischemia/reperfusion can be attenuated by oxygen tension control. Role of oxygen-free radicals and cardiolipin. Biochim Biophys Acta. 2005;1710:78–86.PubMedView ArticleGoogle Scholar
  8. Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg. 2002;10:620–30.PubMedView ArticleGoogle Scholar
  9. Charles AL, Guilbert AS, Guillot M, Talha S, Lejay A, Meyer A, Kindo M, Wolff V, Bouitbir J, Zoll J, Geny B. Muscles susceptibility to ischemia-reperfusion injuries depends on fiber type specific antioxidant level. Front Physiol. 2017;8:52.PubMedPubMed CentralView ArticleGoogle Scholar
  10. Garbaisz D, Turoczi Z, Aranyi P, Fulop A, Rosero O, Hermesz E, Ferencz A, Lotz G, Harsanyi L, Szijarto A. Attenuation of skeletal muscle and renal injury to the lower limb following ischemia-reperfusion using mPTP inhibitor NIM-811. PLoS ONE. 2014;9:e101067.PubMedPubMed CentralView ArticleGoogle Scholar
  11. Jawhar A, Ponelies N, Schild L. Effect of limited ischemia time on the amount and function of mitochondria within human skeletal muscle cells. Eur J Trauma Emerg Surg. 2016;42:767–73.PubMedView ArticleGoogle Scholar
  12. Corona BT, Rivera JC, Owens JG, Wenke JC, Rathbone CR. Volumetric muscle loss leads to permanent disability following extremity trauma. J Rehabil Res Dev. 2015;52:785–92.PubMedView ArticleGoogle Scholar
  13. Novelli GP, Adembri C, Gandini E, Orlandini SZ, Papucci L, Formigli L, Manneschi LI, Quattrone A, Pratesi C, Capaccioli S. Vitamin E protects human skeletal muscle from damage during surgical ischemia-reperfusion. Am J Surg. 1997;173:206–9.PubMedView ArticleGoogle Scholar
  14. Percival TJ, Rasmussen TE. Reperfusion strategies in the management of extremity vascular injury with ischaemia. Br J Surg. 2012;99(Suppl 1):66–74.PubMedView ArticleGoogle Scholar
  15. Barreto-Torres G, Parodi-Rullán R, Javadov S. The role of PPARα in metformin-induced attenuation of mitochondrial dysfunction in acute cardiac ischemia/reperfusion in rats. Int J Mol Sci. 2012;13:7694–709.PubMedPubMed CentralView ArticleGoogle Scholar
  16. Ozkan H, Ekinci S, Uysal B, Akyildiz F, Turkkan S, Ersen O, Koca K, Seven MM. Evaluation and comparison of the effect of hypothermia and ozone on ischemia-reperfusion injury of skeletal muscle in rats. J Surg Res. 2015;196:313–9.PubMedView ArticleGoogle Scholar
  17. Zhu YZ, Wang ZJ, Ho P, Loke YY, Zhu YC, Huang SH, Tan CS, Whiteman M, Lu J, Moore PK. Hydrogen sulfide and its possible roles in myocardial ischemia in experimental rats. J Appl Physiol. 1985;2007(102):261–8.Google Scholar
  18. Hunter JP, Hosgood SA, Patel M, Furness P, Sayers RD, Nicholson ML. Hydrogen sulfide reduces inflammation following abdominal aortic occlusion in rats. Ann Vasc Surg. 2015;29:353–60.PubMedView ArticleGoogle Scholar
  19. Hurtgen BJ, Ward CL, Garg K, Pollot BE, Goldman SM, McKinley TO, Wenke JC, Corona BT. Severe muscle trauma triggers heightened and prolonged local musculoskeletal inflammation and impairs adjacent tibia fracture healing. J Musculoskelet Neuronal Interact. 2016;16:122–34.PubMedPubMed CentralGoogle Scholar
  20. Bełtowski J. Hydrogen sulfide in pharmacology and medicine–an update. Pharmacol Rep. 2015;67:647–58.PubMedView ArticleGoogle Scholar
  21. Módis K, Panopoulos P, Coletta C, Papapetropoulos A, Szabo C. Hydrogen sulfide-mediated stimulation of mitochondrial electron transport involves inhibition of the mitochondrial phosphodiesterase 2A, elevation of cAMP and activation of protein kinase A. Biochem Pharmacol. 2013;86:1311–9.PubMedView ArticleGoogle Scholar
  22. Olson KR, DeLeon ER, Liu F. Controversies and conundrums in hydrogen sulfide biology. Nitric Oxide. 2014;41:11–26.PubMedView ArticleGoogle Scholar
  23. Veeranki S, Tyagi SC. Role of hydrogen sulfide in skeletal muscle biology and metabolism. Nitric Oxide. 2015;46:66–71.PubMedView ArticleGoogle Scholar
  24. Du JT, Li W, Yang JY, Tang CS, Li Q, Jin HF. Hydrogen sulfide is endogenously generated in rat skeletal muscle and exerts a protective effect against oxidative stress. Chin Med J (Engl). 2013;126:930–6.Google Scholar
  25. Carter RN, Morton NM. Cysteine and hydrogen sulphide in the regulation of metabolism: insights from genetics and pharmacology. J Pathol. 2016;238:321–32.PubMedView ArticleGoogle Scholar
  26. Polhemus DJ, Lefer DJ. Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease. Circ Res. 2014;114:730–7.PubMedPubMed CentralView ArticleGoogle Scholar
  27. Polhemus DJ, Calvert JW, Butler J, Lefer DJ. The cardioprotective actions of hydrogen sulfide in acute myocardial infarction and heart failure. Scientifica (Cairo). 2014;2014:768607.Google Scholar
  28. Vitvitsky V, Kabil O, Banerjee R. High turnover rates for hydrogen sulfide allow for rapid regulation of its tissue concentrations. Antioxid Redox Signal. 2012;17:22–31.PubMedPubMed CentralView ArticleGoogle Scholar
  29. Li N, Wang MJ, Jin S, Bai YD, Hou CL, Ma FF, Li XH, Zhu YC. The H2S donor NaHS changes the expression pattern of H2S-producing enzymes after myocardial infarction. Oxid Med Cell Longev. 2016;2016:6492469.PubMedPubMed CentralGoogle Scholar
  30. Xu Z, Prathapasinghe G, Wu N, Hwang SY, Siow YL. Ischemia-reperfusion reduces cystathionine-beta-synthase-mediated hydrogen sulfide generation in the kidney. Am J Physiol Renal Physiol. 2009;297:F27–35.PubMedView ArticleGoogle Scholar
  31. Islam KN, Polhemus DJ, Donnarumma E, Brewster LP, Lefer DJ. Hydrogen sulfide levels and nuclear factor-erythroid 2-related factor 2 (NRF2) activity are attenuated in the setting of critical limb ischemia (CLI). J Am Heart Assoc. 2015;4:e001986.PubMedPubMed CentralView ArticleGoogle Scholar
  32. Liu MH, Zhang Y, He J, Tan TP, Wu SJ, Guo DM, He H, Peng J, Tang ZH, Jiang ZS. Hydrogen sulfide protects H9c2 cardiac cells against doxorubicin-induced cytotoxicity through the PI3 K/Akt/FoxO3a pathway. Int J Mol Med. 2016;37:1661–8.PubMedView ArticleGoogle Scholar
  33. Zhou Y, Wang D, Gao X, Lew K, Richards AM, Wang P. mTORC2 phosphorylation of Akt1: a possible mechanism for hydrogen sulfide-induced cardioprotection. PLoS ONE. 2014;9:e99665.PubMedPubMed CentralView ArticleGoogle Scholar
  34. Zhao H, Lu S, Chai J, Zhang Y, Ma X, Chen J, Guan Q, Wan M, Liu Y. Hydrogen sulfide improves diabetic wound healing in ob/ob mice via attenuating inflammation. J Diabetes Complications. 2017;31:1363–9.PubMedView ArticleGoogle Scholar
  35. Jensen AR, Drucker NA, Khaneki S, Ferkowicz MJ, Markel TA. Hydrogen sulfide improves intestinal recovery following ischemia by endothelial nitric oxide-dependent mechanisms. Am J Physiol Gastrointest Liver Physiol. 2017;312:G450–6.PubMedPubMed CentralView ArticleGoogle Scholar
  36. Ercole F, Mansfeld FM, Kavallaris M, Whittaker MR, Quinn JF, Halls ML, Davis TP. Macromolecular hydrogen sulfide donors trigger spatiotemporally confined changes in cell signaling. Biomacromology. 2016;17:371–83.View ArticleGoogle Scholar
  37. Sun X, Wang W, Dai J, Jin S, Huang J, Guo C, Wang C, Pang L, Wang Y. A long-term and slow-releasing hydrogen sulfide donor protects against myocardial ischemia/reperfusion injury. Sci Rep. 2017;7:3541.PubMedPubMed CentralView ArticleGoogle Scholar
  38. Minamishima S, Bougaki M, Sips PY, Yu JD, Minamishima YA, Elrod JW, Lefer DJ, Bloch KD, Ichinose F. Hydrogen sulfide improves survival after cardiac arrest and cardiopulmonary resuscitation via a nitric oxide synthase 3-dependent mechanism in mice. Circulation. 2009;120:888–96.PubMedPubMed CentralView ArticleGoogle Scholar
  39. Xie H, Xu Q, Jia J, Ao G, Sun Y, Hu L, Alkayed NJ, Wang C, Cheng J. Hydrogen sulfide protects against myocardial ischemia and reperfusion injury by activating AMP-activated protein kinase to restore autophagic flux. Biochem Biophys Res Commun. 2015;458:632–8.PubMedView ArticleGoogle Scholar
  40. Schiaffino S, Mammucari C. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skelet Muscle. 2011;1:4.PubMedPubMed CentralView ArticleGoogle Scholar
  41. Yong QC, Lee SW, Foo CS, Neo KL, Chen X, Bian JS. Endogenous hydrogen sulphide mediates the cardioprotection induced by ischemic postconditioning. Am J Physiol Heart Circ Physiol. 2008;295:H1330–40.PubMedView ArticleGoogle Scholar
  42. Wang D, Ma Y, Li Z, Kang K, Sun X, Pan S, Wang J, Pan H, Liu L, Liang D, Jiang H. The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice. Autophagy. 2012;8:954–62.PubMedPubMed CentralView ArticleGoogle Scholar
  43. Karwi QG, Whiteman M, Wood ME, Torregrossa R, Baxter GF. Pharmacological postconditioning against myocardial infarction with a slow-releasing hydrogen sulfide donor, GYY4137. Pharmacol Res. 2016;111:442–51.View ArticleGoogle Scholar
  44. Narne P, Pandey V, Phanithi PB. Role of nitric oxide and hydrogen sulfide in ischemic stroke and the emergent epigenetic underpinnings. Mol Neurobiol. 2018. https://doi.org/10.1007/s12035-018-1141-6.View ArticlePubMedGoogle Scholar
  45. Cao HH, Chu JH, Kwan HY, Su T, Yu H, Cheng CY, Fu XQ, Guo H, Li T, Tse AK, et al. Inhibition of the STAT3 signaling pathway contributes to apigenin-mediated anti-metastatic effect in melanoma. Sci Rep. 2016;6:21731.PubMedPubMed CentralView ArticleGoogle Scholar
  46. Yuan S, Shen X, Kevil CG. Beyond a gasotransmitter: hydrogen sulfide and polysulfide in cardiovascular health and immune response. Antioxid Redox Signal. 2017;27(10):634–53.PubMedPubMed CentralView ArticleGoogle Scholar
  47. Borselli C, Storrie H, Benesch-Lee F, Shvartsman D, Cezar C, Lichtman JW, Vandenburgh HH, Mooney DJ. Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors. Proc Natl Acad Sci USA. 2010;107:3287–92.PubMedView ArticleGoogle Scholar
  48. Langston JW, Toombs CF. Defining the minimally effective dose and schedule for parenteral hydrogen sulfide: long-term benefits in a rat model of hindlimb ischemia. Med Gas Res. 2015;5:5.PubMedPubMed CentralView ArticleGoogle Scholar
  49. Deasy BM, Feduska JM, Payne TR, Li Y, Ambrosio F, Huard J. Effect of VEGF on the regenerative capacity of muscle stem cells in dystrophic skeletal muscle. Mol Ther. 2009;17:1788–98.PubMedPubMed CentralView ArticleGoogle Scholar
  50. Shvartsman D, Storrie-White H, Lee K, Kearney C, Brudno Y, Ho N, Cezar C, McCann C, Anderson E, Koullias J, et al. Sustained delivery of VEGF maintains innervation and promotes reperfusion in ischemic skeletal muscles via NGF/GDNF signaling. Mol Ther. 2014;22:1243–53.PubMedPubMed CentralView ArticleGoogle Scholar
  51. Kang Z, Jiang W, Luan H, Zhao F, Zhang S. Cornin induces angiogenesis through PI3 K-Akt-eNOS-VEGF signaling pathway. Food Chem Toxicol. 2013;58:340–6.PubMedView ArticleGoogle Scholar
  52. Kroll J, Waltenberger J. VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochem Biophys Res Commun. 1998;252:743–6.PubMedView ArticleGoogle Scholar
  53. Jang H, Oh MY, Kim YJ, Choi IY, Yang HS, Ryu WS, Lee SH, Yoon BW. Hydrogen sulfide treatment induces angiogenesis after cerebral ischemia. J Neurosci Res. 2014;92:1520–8.PubMedView ArticleGoogle Scholar
  54. Wang MJ, Cai WJ, Li N, Ding YJ, Chen Y, Zhu YC. The hydrogen sulfide donor NaHS promotes angiogenesis in a rat model of hind limb ischemia. Antioxid Redox Signal. 2010;12:1065–77.PubMedView ArticleGoogle Scholar
  55. Kondo K, Bhushan S, King AL, Prabhu SD, Hamid T, Koenig S, Murohara T, Predmore BL, Gojon G, Wang R, et al. H2S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation. 2013;127:1116–27.PubMedPubMed CentralView ArticleGoogle Scholar
  56. King AL, Polhemus DJ, Bhushan S, Otsuka H, Kondo K, Nicholson CK, Bradley JM, Islam KN, Calvert JW, Tao YX, et al. Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent. Proc Natl Acad Sci USA. 2014;111:3182–7.PubMedView ArticleGoogle Scholar
  57. Hayashida R, Kondo K, Morita S, Unno K, Shintani S, Shimizu Y, Calvert JW, Shibata R, Murohara T. Diallyl trisulfide augments ischemia-induced angiogenesis via an endothelial nitric oxide synthase-dependent mechanism. Circ J. 2017;81:870–8.PubMedView ArticleGoogle Scholar
  58. Chattopadhyay A, Bandyopadhyay D. Vitamin E in the prevention of ischemic heart disease. Pharmacol Rep. 2006;58:179–87.PubMedGoogle Scholar
  59. Saleh NK, Saleh HA. Protective effects of vitamin E against myocardial ischemia/reperfusion injury in rats. Saudi Med J. 2010;31:142–7.PubMedGoogle Scholar
  60. Kimura H. Signaling molecules: hydrogen sulfide and polysulfide. Antioxid Redox Signal. 2015;22:362–76.PubMedPubMed CentralView ArticleGoogle Scholar
  61. Kolluru GK, Shen X, Kevil CG. A tale of two gases: NO and H2S, foes or friends for life? Redox Biol. 2013;1:313–8.PubMedPubMed CentralView ArticleGoogle Scholar
  62. Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010;90:1383–435.PubMedView ArticleGoogle Scholar
  63. Lesnefsky EJ, Hoppel CL. Oxidative phosphorylation and aging. Ageing Research Reviews. 2006;5:402–33.PubMedView ArticleGoogle Scholar
  64. Hernández JS, Barreto-Torres G, Kuznetsov AV, Khuchua Z, Javadov S. Crosstalk between AMPK activation and angiotensin II-induced hypertrophy in cardiomyocytes: the role of mitochondria. J Cell Mol Med. 2014;18:709–20.PubMedPubMed CentralView ArticleGoogle Scholar
  65. Korth U, Merkel G, Fernandez FF, Jandewerth O, Dogan G, Koch T, van Ackern K, Weichel O, Klein J. Tourniquet-induced changes of energy metabolism in human skeletal muscle monitored by microdialysis. Anesthesiology. 2000;93:1407–12.PubMedView ArticleGoogle Scholar
  66. Walters AM, Porter GA, Brookes PS. Mitochondria as a drug target in ischemic heart disease and cardiomyopathy. Circ Res. 2012;111:1222–36.PubMedPubMed CentralView ArticleGoogle Scholar
  67. Javadov S, Karmazyn M. Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection. Cell Physiol Biochem. 2007;20:1–22.PubMedView ArticleGoogle Scholar
  68. Tompkins AJ, Burwell LS, Digerness SB, Zaragoza C, Holman WL, Brookes PS. Mitochondrial dysfunction in cardiac ischemia-reperfusion injury: ROS from complex I, without inhibition. Biochim Biophys Acta. 2006;1762:223–31.PubMedView ArticleGoogle Scholar
  69. Pipinos II, Swanson SA, Zhu Z, Nella AA, Weiss DJ, Gutti TL, McComb RD, Baxter BT, Lynch TG, Casale GP. Chronically ischemic mouse skeletal muscle exhibits myopathy in association with mitochondrial dysfunction and oxidative damage. Am J Physiol Regul Integr Comp Physiol. 2008;295:R290–6.PubMedPubMed CentralView ArticleGoogle Scholar
  70. Narne P, Pandey V, Phanithi PB. Interplay between mitochondrial metabolism and oxidative stress in ischemic stroke: an epigenetic connection. Mol Cell Neurosci. 2017;82:176–94.PubMedView ArticleGoogle Scholar
  71. Flagg TP, Enkvetchakul D, Koster JC, Nichols CG. Muscle KATP channels: recent insights to energy sensing and myoprotection. Physiol Rev. 2010;90:799–829.PubMedPubMed CentralView ArticleGoogle Scholar
  72. Li H, Zhang C, Sun W, Li L, Wu B, Bai S, Zhong X, Wang R, Wu L, Xu C. Exogenous hydrogen sulfide restores cardioprotection of ischemic post-conditioning via inhibition of mPTP opening in the aging cardiomyocytes. Cell Biosci. 2015;5:43.PubMedPubMed CentralView ArticleGoogle Scholar
  73. Liang W, Chen J, Mo L, Ke X, Zhang W, Zheng D, Pan W, Wu S, Feng J, Song M, Liao X. ATP-sensitive K+ channels contribute to the protective effects of exogenous hydrogen sulfide against high glucose-induced injury in H9c2 cardiac cells. Int J Mol Med. 2016;37:763–72.PubMedView ArticleGoogle Scholar
  74. Du Q, Wang C, Zhang N, Li G, Zhang M, Li L, Zhang Q, Zhang J. In vivo study of the effects of exogenous hydrogen sulfide on lung mitochondria in acute lung injury in rats. BMC Anesthesiol. 2014;14:117.PubMedPubMed CentralView ArticleGoogle Scholar
  75. Lu M, Zhao FF, Tang JJ, Su CJ, Fan Y, Ding JH, Bian JS, Hu G. The neuroprotection of hydrogen sulfide against MPTP-induced dopaminergic neuron degeneration involves uncoupling protein 2 rather than ATP-sensitive potassium channels. Antioxid Redox Signal. 2012;17:849–59.PubMedPubMed CentralView ArticleGoogle Scholar
  76. Kida K, Yamada M, Tokuda K, Marutani E, Kakinohana M, Kaneki M, Ichinose F. Inhaled hydrogen sulfide prevents neurodegeneration and movement disorder in a mouse model of Parkinson’s disease. Antioxid Redox Signal. 2011;15:343–52.PubMedPubMed CentralView ArticleGoogle Scholar
  77. Inagaki N, Inazawa J, Seino S. cDNA sequence, gene structure, and chromosomal localization of the human ATP-sensitive potassium channel, uKATP-1, gene (KCNJ8). Genomics. 1995;30:102–4.PubMedView ArticleGoogle Scholar
  78. Inagaki N, Gonoi T, Clement JP, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science. 1995;270:1166–70.PubMedView ArticleGoogle Scholar
  79. Gade AR, Kang M, Akbarali HI. Hydrogen sulfide as an allosteric modulator of ATP-sensitive potassium channels in colonic inflammation. Mol Pharmacol. 2013;83:294–306.PubMedPubMed CentralView ArticleGoogle Scholar
  80. Zhang HT, Zhang T, Chai M, Sun JJ, Yu XY, Liu CZ, Huang CC. Effect of tobacco smoke on hydrogen sulfide-induced rat thoracic aorta relaxation. Braz J Med Biol Res. 2017;50:e5592.PubMedPubMed CentralGoogle Scholar
  81. Berdeaux R, Stewart R. cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration. Am J Physiol Endocrinol Metab. 2012;303:E1–17.PubMedPubMed CentralView ArticleGoogle Scholar
  82. Shaikh D, Zhou Q, Chen T, Ibe JC, Raj JU, Zhou G. cAMP-dependent protein kinase is essential for hypoxia-mediated epithelial-mesenchymal transition, migration, and invasion in lung cancer cells. Cell Signal. 2012;24:2396–406.PubMedView ArticleGoogle Scholar
  83. Zhang Z, Apse K, Pang J, Stanton RC. High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aortic endothelial cells. J Biol Chem. 2000;275:40042–7.PubMedView ArticleGoogle Scholar
  84. Beauchamp RO, Bus JS, Popp JA, Boreiko CJ, Andjelkovich DA. A critical review of the literature on hydrogen sulfide toxicity. Crit Rev Toxicol. 1984;13:25–97.PubMedView ArticleGoogle Scholar
  85. Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation-like state in mice. Science. 2005;308:518.PubMedView ArticleGoogle Scholar
  86. Aslami H, Schultz MJ, Juffermans NP. Potential applications of hydrogen sulfide-induced suspended animation. Curr Med Chem. 2009;16:1295–303.PubMedView ArticleGoogle Scholar
  87. Aslami H, Juffermans NP. Induction of a hypometabolic state during critical illness—a new concept in the ICU? Neth J Med. 2010;68:190–8.PubMedGoogle Scholar
  88. Bos EM, Leuvenink HG, Snijder PM, Kloosterhuis NJ, Hillebrands JL, Leemans JC, Florquin S, van Goor H. Hydrogen sulfide-induced hypometabolism prevents renal ischemia/reperfusion injury. J Am Soc Nephrol. 2009;20:1901–5.PubMedPubMed CentralView ArticleGoogle Scholar
  89. Dugbartey GJ, Bouma HR, Saha MN, Lobb I, Henning RH, Sener A. A hibernation-like state for transplantable organs: is hydrogen sulfide therapy the future of organ preservation? Antioxid Redox Signal. 2017;28(16):1503–15.PubMedView ArticleGoogle Scholar
  90. Shi S, Li QS, Li H, Zhang L, Xu M, Cheng JL, Peng CH, Xu CQ, Tian Y. Anti-apoptotic action of hydrogen sulfide is associated with early JNK inhibition. Cell Biol Int. 2009;33:1095–101.PubMedView ArticleGoogle Scholar
  91. Guan Q, Zhang Y, Yu C, Liu Y, Gao L, Zhao J. Hydrogen sulfide protects against high-glucose-induced apoptosis in endothelial cells. J Cardiovasc Pharmacol. 2012;59:188–93.PubMedView ArticleGoogle Scholar
  92. Dai HB, Xu MM, Lv J, Ji XJ, Zhu SH, Ma RM, Miao XL, Duan ML. Mild hypothermia combined with hydrogen sulfide treatment during resuscitation reduces hippocampal neuron apoptosis Via NR2A, NR2B, and PI3K-Akt signaling in a rat model of cerebral ischemia-reperfusion injury. Mol Neurobiol. 2016;53:4865–73.PubMedView ArticleGoogle Scholar
  93. Ji K, Xue L, Cheng J, Bai Y. Preconditioning of H2S inhalation protects against cerebral ischemia/reperfusion injury by induction of HSP70 through PI3K/Akt/Nrf2 pathway. Brain Res Bull. 2016;121:68–74.PubMedView ArticleGoogle Scholar
  94. Biermann J, Lagrèze WA, Schallner N, Schwer CI, Goebel U. Inhalative preconditioning with hydrogen sulfide attenuated apoptosis after retinal ischemia/reperfusion injury. Mol Vis. 2011;17:1275–86.PubMedPubMed CentralGoogle Scholar
  95. Yao LL, Huang XW, Wang YG, Cao YX, Zhang CC, Zhu YC. Hydrogen sulfide protects cardiomyocytes from hypoxia/reoxygenation-induced apoptosis by preventing GSK-3beta-dependent opening of mPTP. Am J Physiol Heart Circ Physiol. 2010;298:H1310–9.PubMedView ArticleGoogle Scholar
  96. Elrod JW, Calvert JW, Morrison J, Doeller JE, Kraus DW, Tao L, Jiao X, Scalia R, Kiss L, Szabo C, et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci USA. 2007;104:15560–5.PubMedView ArticleGoogle Scholar
  97. Jeschke MG, Finnerty CC, Herndon DN, Song J, Boehning D, Tompkins RG, Baker HV, Gauglitz GG. Severe injury is associated with insulin resistance, endoplasmic reticulum stress response, and unfolded protein response. Ann Surg. 2012;255:370–8.PubMedPubMed CentralView ArticleGoogle Scholar
  98. Yao X, Wigginton JG, Maass DL, Ma L, Carlson D, Wolf SE, Minei JP, Zang QS. Estrogen-provided cardiac protection following burn trauma is mediated through a reduction in mitochondria-derived DAMPs. Am J Physiol Heart Circ Physiol. 2014;306:H882–94.PubMedView ArticleGoogle Scholar
  99. Cheng P, Wang F, Chen K, Shen M, Dai W, Xu L, Zhang Y, Wang C, Li J, Yang J, et al. Hydrogen sulfide ameliorates ischemia/reperfusion-induced hepatitis by inhibiting apoptosis and autophagy pathways. Mediators Inflamm. 2014;2014:935251.PubMedPubMed CentralGoogle Scholar
  100. Liesa M, Palacín M, Zorzano A. Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 2009;89:799–845.PubMedView ArticleGoogle Scholar
  101. Zhang Q, Fu H, Zhang H, Xu F, Zou Z, Liu M, Wang Q, Miao M, Shi X. Hydrogen sulfide preconditioning protects rat liver against ischemia/reperfusion injury by activating Akt-GSK-3β signaling and inhibiting mitochondrial permeability transition. PLoS ONE. 2013;8:e74422.PubMedPubMed CentralView ArticleGoogle Scholar
  102. Jha S, Calvert JW, Duranski MR, Ramachandran A, Lefer DJ. Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling. Am J Physiol Heart Circ Physiol. 2008;295:H801–6.PubMedPubMed CentralView ArticleGoogle Scholar
  103. Boroujeni MB, Khayat ZK, Anbari K, Niapour A, Gholami M, Gharravi AM. Coenzyme Q10 protects skeletal muscle from ischemia-reperfusion through the NF-kappa B pathway. Perfusion. 2017;32:372–7.PubMedView ArticleGoogle Scholar
  104. Irie H, Kato T, Ikebe K, Tsuchida T, Oniki Y, Takagi K. Antioxidant effect of MCI-186, a new Free-Radical scavenger, on ischemia-reperfusion injury in a rat hindlimb amputation model. J Surg Res. 2004;120:312–9.PubMedView ArticleGoogle Scholar
  105. Sivarajah A, Collino M, Yasin M, Benetti E, Gallicchio M, Mazzon E, Cuzzocrea S, Fantozzi R, Thiemermann C. Anti-apoptotic and anti-inflammatory effects of hydrogen sulfide in a rat model of regional myocardial I/R. Shock. 2009;31:267–74.PubMedView ArticleGoogle Scholar
  106. Wu Z, Peng H, Du Q, Lin W, Liu Y. GYY4137, a hydrogen sulfide-releasing molecule, inhibits the inflammatory response by suppressing the activation of nuclear factor-kappa B and mitogen-activated protein kinases in Coxsackie virus B3-infected rat cardiomyocytes. Mol Med Rep. 2015;11:1837–44.PubMedView ArticleGoogle Scholar
  107. Li C, Liu Y, Tang P, Liu P, Hou C, Zhang X, Chen L, Zhang L, Gu C. Hydrogen sulfide prevents OGD/R-induced apoptosis by suppressing the phosphorylation of p38 and secretion of IL-6 in PC12 cells. NeuroReport. 2016;27:230–4.PubMedView ArticleGoogle Scholar
  108. Henderson PW, Singh SP, Weinstein AL, Nagineni V, Rafii DC, Kadouch D, Krijgh DD, Spector JA. Therapeutic metabolic inhibition: hydrogen sulfide significantly mitigates skeletal muscle ischemia reperfusion injury in vitro and in vivo. Plast Reconstr Surg. 2010;126:1890–8.PubMedView ArticleGoogle Scholar
  109. Henderson PW, Jimenez N, Ruffino J, Sohn AM, Weinstein AL, Krijgh DD, Reiffel AJ, Spector JA. Therapeutic delivery of hydrogen sulfide for salvage of ischemic skeletal muscle after the onset of critical ischemia. J Vasc Surg. 2011;53:785–91.PubMedView ArticleGoogle Scholar
  110. Tripatara P, Patel NS, Collino M, Gallicchio M, Kieswich J, Castiglia S, Benetti E, Stewart KN, Brown PA, Yaqoob MM, et al. Generation of endogenous hydrogen sulfide by cystathionine gamma-lyase limits renal ischemia/reperfusion injury and dysfunction. Lab Invest. 2008;88:1038–48.PubMedView ArticleGoogle Scholar
  111. Tran TP, Tu H, Liu J, Muelleman RL, Li YL. Mitochondria-derived superoxide links to tourniquet-induced apoptosis in mouse skeletal muscle. PLoS ONE. 2012;7:e43410.PubMedPubMed CentralView ArticleGoogle Scholar
  112. Mansour Z, Charles AL, Bouitbir J, Pottecher J, Kindo M, Mazzucotelli JP, Zoll J, Geny B. Remote and local ischemic postconditioning further impaired skeletal muscle mitochondrial function after ischemia-reperfusion. J Vasc Surg. 2012;56(774–782):e771.Google Scholar
  113. Aslami H, Pulskens WP, Kuipers MT, Bos AP, van Kuilenburg AB, Wanders RJ, Roelofsen J, Roelofs JJ, Kerindongo RP, Beurskens CJ, et al. Hydrogen sulfide donor NaHS reduces organ injury in a rat model of pneumococcal pneumosepsis, associated with improved bio-energetic status. PLoS ONE. 2013;8:e63497.PubMedPubMed CentralView ArticleGoogle Scholar
  114. Kang B, Hong J, Xiao J, Zhu X, Ni X, Zhang Y, He B, Wang Z. Involvement of miR-1 in the protective effect of hydrogen sulfide against cardiomyocyte apoptosis induced by ischemia/reperfusion. Mol Biol Rep. 2014;41:6845–53.PubMedView ArticleGoogle Scholar
  115. Toldo S, Das A, Mezzaroma E, Chau VQ, Marchetti C, Durrant D, Samidurai A, Van Tassell BW, Yin C, Ockaili RA, et al. Induction of microRNA-21 with exogenous hydrogen sulfide attenuates myocardial ischemic and inflammatory injury in mice. Circ Cardiovasc Genet. 2014;7:311–20.PubMedPubMed CentralView ArticleGoogle Scholar
  116. Chen Z, Zhang Z, Zhang D, Li H, Sun Z. Hydrogen sulfide protects against TNF-α induced neuronal cell apoptosis through miR-485-5p/TRADD signaling. Biochem Biophys Res Commun. 2016;478:1304–9.PubMedView ArticleGoogle Scholar
  117. Zhou X, An G, Chen J. Hydrogen sulfide improves left ventricular function in smoking rats via regulation of apoptosis and autophagy. Apoptosis. 2014;19:998–1005.PubMedView ArticleGoogle Scholar
  118. Guo C, Liang F, Shah Masood W, Yan X. Hydrogen sulfide protected gastric epithelial cell from ischemia/reperfusion injury by Keap1 s-sulfhydration, MAPK dependent anti-apoptosis and NF-κB dependent anti-inflammation pathway. Eur J Pharmacol. 2014;725:70–8.PubMedView ArticleGoogle Scholar
  119. Kuo WW, Wang WJ, Tsai CY, Way CL, Hsu HH, Chen LM. Diallyl trisufide (DATS) suppresses high glucose-induced cardiomyocyte apoptosis by inhibiting JNK/NFκB signaling via attenuating ROS generation. Int J Cardiol. 2013;168:270–80.PubMedView ArticleGoogle Scholar
  120. Cheng Z, Garikipati VN, Nickoloff E, Wang C, Polhemus DJ, Zhou J, Benedict C, Khan M, Verma SK, Rabinowitz JE, et al. Restoration of hydrogen sulfide production in diabetic mice improves reparative function of bone marrow cells. Circulation. 2016;134:1467–83.PubMedPubMed CentralView ArticleGoogle Scholar
  121. Benavides GA, Squadrito GL, Mills RW, Patel HD, Isbell TS, Patel RP, Darley-Usmar VM, Doeller JE, Kraus DW. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci USA. 2007;104:17977–82.PubMedView ArticleGoogle Scholar
  122. Hancock HM, Stannard A, Burkhardt GE, Williams K, Dixon P, Cowart J, Spencer J, Rasmussen TE. Hemorrhagic shock worsens neuromuscular recovery in a porcine model of hind limb vascular injury and ischemia-reperfusion. J Vasc Surg. 2011;53:1052–62 (discussion 1062).PubMedView ArticleGoogle Scholar
  123. Villamaria CY, Fries CA, Spencer JR, Roth M, Davis MR. Hydrogen sulfide mitigates reperfusion injury in a porcine model of vascularized composite autotransplantation. Ann Plast Surg. 2014;72:594–8.PubMedView ArticleGoogle Scholar
  124. Wilson HM, Welikson RE, Luo J, Kean TJ, Cao B, Dennis JE, Allen MD. Can cytoprotective cobalt protoporphyrin protect skeletal muscle and muscle-derived stem cells from ischemic injury? Clin Orthop Relat Res. 2015;473:2908–19.PubMedPubMed CentralView ArticleGoogle Scholar
  125. Knapp J, Heinzmann A, Schneider A, Padosch SA, Böttiger BW, Teschendorf P, Popp E. Hypothermia and neuroprotection by sulfide after cardiac arrest and cardiopulmonary resuscitation. Resuscitation. 2011;82:1076–80.PubMedView ArticleGoogle Scholar
  126. Dai HB, Ji X, Zhu SH, Hu YM, Zhang LD, Miao XL, Ma RM, Duan ML, Li WY. Hydrogen sulphide and mild hypothermia activate the CREB signaling pathway and prevent ischemia-reperfusion injury. BMC Anesthesiol. 2015;15:119.PubMedPubMed CentralView ArticleGoogle Scholar

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