Protective mechanisms of hydrogen sulfide in myocardial ischemia

Hydrogen sulfide (H₂S), which has been identified as the third gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO), plays an important role in maintaining homeostasis in the cardiovascular system. Endogenous H₂S is produced mainly by three endogenous enzymes: cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfur transferase. Numerous studies have shown that H₂S has a significant protective role in myocardial ischemia. The mechanisms by which H₂S affords cardioprotection include the antifibrotic and antiapoptotic effects, regulation of ion channels, protection of mitochondria, reduction of oxidative stress and inflammatory response, regulation of microRNA expression, and promotion of angiogenesis. Amplification of NO- and CO-mediated signaling through crosstalk between H₂S, NO, and CO may also contribute to the cardioprotective effect. Exogenous H₂S donors are expected to become effective drugs for the treatment of cardiovascular diseases. This review article focuses on the protective mechanisms and potential therapeutic applications of H₂S in myocardial ischemia.     

Hydrogen Sulfide Regulates Cardiovascular Function by Influencing the Excitability of Subfornical Organ Neurons

Hydrogen sulfide (H₂S), a gasotransmitter endogenously found in the central nervous system, has recently been suggested to act as a signalling molecule in the brain having beneficial effects on cardiovascular function. This study was thus undertaken to investigate the effect of NaHS (an H₂S donor) in the subfornical organ (SFO), a central nervous system site important to blood pressure regulation. We used male Sprague-Dawley rats for both in vivo and in vitro experiments. We first used RT-PCR to confirm our previous microarray analyses showing that mRNAs for the enzymes required to produce H₂S are expressed in the SFO. We then used microinjection techniques to investigate the physiological effects of NaHS in SFO, and found that NaHS microinjection (5 nmol) significantly increased blood pressure (mean AUC = 853.5±105.7 mmHg*s, n = 5). Further, we used patch-clamp electrophysiology and found that 97.8% (88 of 90) of neurons depolarized in response to NaHS. This response was found to be concentration dependent with an EC₅₀ of 35.6 µM. Coupled with the depolarized membrane potential, we observed an overall increase in neuronal excitability using an analysis of rheobase and action potential firing patterns. This study has provided the first evidence of NaHS and thus H₂S actions and their cellular correlates in SFO, implicating this brain area as a site where H₂S may act to control blood pressure.     

Hydrogen sulfide: its production,release and functions

Hydrogen sulfide (H₂S), which is a well-known toxic gas, has been recognized as a signal molecule as well as a cytoprotectant. It is produced by three enzymes, cystathionine β-synthase, cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase along with cysteine aminotransferase. In addition to an immediate release of H₂S from producing enzymes, it can be stored as bound sulfane sulfur, which may release H₂S in response to physiological stimuli. As a signal molecule, it modulates neuronal transmission, relaxes smooth muscle, regulates release of insulin and is involved in inflammation. Because of its reputation as a toxic gas, the function as a cytoprotectant has been overlooked: the nervous system and cardiovascular system are protected from oxidative stress. In this review, enzymatic production, release mechanism and functions of H₂S are focused on.     

H2S and its role in redox signaling

Hydrogen sulfide (H₂S) has emerged as an important gaseous signaling molecule that is produced endogenously by enzymes in the sulfur metabolic network. H₂S exerts its effects on multiple physiological processes important under both normal and pathological conditions. These functions include neuromodulation, regulation of blood pressure and cardiac function, inflammation, cellular energetics and apoptosis. Despite the recognition of its biological importance and its beneficial effects, the mechanism of H₂S action and the regulation of its tissue levels remain unclear in part owing to its chemical and physical properties that render handling and analysis challenging. Furthermore, the multitude of potential H₂S effects has made it difficult to dissect its signaling mechanism and to identify specific targets. In this review, we focus on H₂S metabolism and provide an overview of the recent literature that sheds some light on its mechanism of action in cellular redox signaling in health and disease. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.     

Role of hydrogen sulfide in secondary neuronal injury

In acute neuronal insult events, such as stroke, traumatic brain injury, and spinal cord injury, pathological processes of secondary neuronal injury play a key role in the severity of insult and clinical prognosis. Along with nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H₂S) is regarded as the third gasotransmitter and endogenous neuromodulator and plays multiple roles in the central nervous system under physiological and pathological states, especially in secondary neuronal injury. The endogenous level of H₂S in the brain is significantly higher than that in peripheral tissues, and is mainly formed by cystathionine β-synthase (CBS) in astrocytes and released in response to neuronal excitation. The mechanism of secondary neuronal injury exacerbating the damage caused by the initial insult includes microcirculation failure, glutamate-mediated excitotoxicity, oxidative stress, inflammatory responses, neuronal apoptosis and calcium overload. H₂S dilates cerebral vessels by activating smooth muscle cell plasma membrane ATP-sensitive K channels (K_ATP channels). This modification occurs on specific cysteine residues of the K_ATP channel proteins which are S-sulfhydrated. H₂S counteracts glutamate-mediated excitotoxicity by inducing astrocytes to intake more glutamate from the extracellular space and thus increasing glutathione in neurons. In addition, H₂S protects neurons from secondary neuronal injury by functioning as an anti-oxidant, anti-inflammatory and anti-apoptotic mediator. However, there are still some reports suggest that H₂S elevates neuronal Ca²⁺ concentration and may contribute to the formation of calcium overload in secondary neuronal injury. H₂S also elicits calcium waves in primary cultures of astrocytes and may mediate signals between neurons and glia. Consequently, further exploration of the molecular mechanisms of H₂S in secondary neuronal injury will provide important insights into its potential therapeutic uses for the treatment of acute neuronal insult events.     

Hydrogen sulfide,a signaling molecule in plant stress responses

Gaseous molecules, such as hydrogen sulfide(H_2S)and nitric oxide(NO), are crucial players in cellular and(patho)physiological processes in biological systems. The biological functions of these gaseous molecules, which were first discovered and identified as gasotransmitters in animals, have received unprecedented attention from plant scientists in recent decades. Researchers have arrived at the consensus that H_2S is synthesized endogenously and serves as a signaling molecule throughout the plant life cycle.However, the mechanisms of H_2S action in redox biology is still largely unexplored. This review highlights what we currently know about the characteristics and biosynthesis of H_2S in plants. Additionally,we summarize the role of H_2S in plant resistance to abiotic stress. Moreover, we propose and discuss possible redox-dependent mechanisms by which H_2S regulates plant physiology.     

Hydrogen sulphide ameliorating skeletal muscle atrophy in db/db mice via Muscle RING finger 1 S‐sulfhydration

Muscle atrophy occurs in many pathological states, including cancer, diabetes and sepsis, whose results primarily from accelerated protein degradation and activation of the ubiquitin‐proteasome pathway. Expression of Muscle RING finger 1 (MuRF1), an E3 ubiquitin ligase, was increased to induce the loss of muscle mass in diabetic condition. However, hydrogen sulphide (H₂S) plays a crucial role in the variety of physiological functions, including antihypertension, antiproliferation and antioxidant. In this study, db/db mice and C2C12 myoblasts treated by high glucose and palmitate and oleate were chose as animal and cellular models. We explored how exogenous H₂S attenuated the degradation of skeletal muscle via the modification of MuRF1 S‐sulfhydration in db/db mice. Our results show cystathionine‐r‐lyase expression, and H₂S level in skeletal muscle of db/db mice was reduced. Simultaneously, exogenous H₂S could alleviate ROS production and reverse expression of ER stress protein markers. Exogenous H₂S could decrease the ubiquitination level of MYOM1 and MYH4 in db/db mice. In addition, exogenous H₂S reduced the interaction between MuRF1 with MYOM1 and MYH4 via MuRF1 S‐sulfhydration. Based on these results, we establish that H₂S prevented the degradation of skeletal muscle via MuRF1 S‐sulfhydration at the site of Cys44 in db/db mice.     

Endogenous hydrogen sulfide is involved in the pathogenesis of atherosclerosis

Atherosclerosis is a chronic, complex, and progressive pathological process in large and medium sized arteries. The exact mechanism of this process remains unclear. Hydrogen sulfide (H₂S), a novel gasotransmitter, was confirmed as playing a major role in the pathogenesis of many cardiovascular diseases. It plays a role in vascular smooth muscle cell (VSMC) proliferation and apoptosis, participates in the progress of hyperhomocysteinemia (HHCY), inhibits atherogenic modification of LDL, interferes with vascular calcification, intervenes with platelet function, and there are interactions between H₂S and inflammatory processes. The role of H₂S in atherosclerotic pathogenesis highlights the mysteries of atherosclerosis and inspires the search for innovative therapeutic strategies. Here, we review the studies to date that have considered the role of H₂S in atherosclerosis.     

Up Regulation of cystathione γ lyase and Hydrogen Sulphide in the Myocardium Inhibits the Progression of Isoproterenol–Caffeine Induced Left Ventricular Hypertrophy in Wistar Kyoto Rats

Hydrogen sulphide (H₂S) is an emerging molecule in many cardiovascular complications but its role in left ventricular hypertrophy (LVH) is unknown. The present study explored the effect of exogenous H₂S administration in the regression of LVH by modulating oxidative stress, arterial stiffness and expression of cystathione γ lyase (CSE) in the myocardium. Animals were divided into four groups: Control, LVH, Control-H₂S and LVH-H₂S. LVH was induced by administering isoprenaline (5mg/kg, every 72 hours, S/C) and caffeine in drinking water (62mg/L) for 2 weeks. Intraperitoneal NaHS, 56μM/kg/day for 5 weeks, was given as an H₂S donor. Myocardial expression of Cystathione γ lyase (CSE) mRNA was quantified using real time polymerase chain reaction (qPCR).There was a 3 fold reduction in the expression of myocardial CSE mRNA in LVH but it was up regulated by 7 and 4 fold in the Control-H₂S and LVH-H₂S myocardium, respectively. Systolic blood pressure, mean arterial pressure, pulse wave velocity were reduced (all P<0.05) in LVH-H₂S when compared to the LVH group. Heart, LV weight, myocardial thickness were reduced while LV internal diameter was increased (all P<0.05) in the LVH-H₂S when compared to the LVH group. Exogenous administration of H₂S in LVH increased superoxide dismutase, glutathione and total antioxidant capacity but significantly reduced (all P<0.05) plasma malanodialdehyde in the LVH-H₂S compared to the LVH group. The renal cortical blood perfusion increased by 40% in LVH-H₂S as compared to the LVH group. Exogenous administration of H₂S suppressed the progression of LVH which was associated with an up regulation of myocardial CSE mRNA/ H₂S and a reduction in pulse wave velocity with a blunting of systemic hemodynamic. This CSE/H₂S pathway exhibits an antihypertrophic role by antagonizing the hypertrophic actions of angiotensin II(Ang II) and noradrenaline (NA) but attenuates oxidative stress and improves pulse wave velocity which helps to suppress LVH. Exogenous administration of H₂S augmented the reduced renal cortical blood perfusion in the LVH state.     

Expression of cystathionine β-synthase and cystathionine γ-lyase in human pregnant myometrium and their roles in the control of uterine contractility

Background

Human uterus undergoes distinct molecular and functional changes during pregnancy and parturition. Hydrogen sulfide (H₂S) has recently been shown to play a key role in the control of smooth muscle tension. The role of endogenous H₂S produced locally in the control of uterine contractility during labour is unknown.

Methodology/Principal Findings

Human myometrium biopsies were obtained from pregnant women undergoing cesarean section at term. Immunohistochemistry analysis showed that cystathionine-γ-lyase (CSE) and cystathionine-β-synthetase (CBS), the principle enzymes responsible for H₂S generation, were mainly localized to smooth muscle cells of human pregnant myometrium. The mRNA and protein expression of CBS as well as H₂S production rate were down-regulated in labouring tissues compared to nonlabouring tissues. Cumulative administration of L-cysteine (10⁻⁷–10⁻² mol/L), a precursor of H₂S, caused a dose-dependent decrease in the amplitude of spontaneous contractions in nonlabouring and labouring myometrium strips. L-cysteine at high concentration (10⁻³ mol/L) increased the frequency of spontaneous contractions and induced tonic contraction. These effects of L-cysteine were blocked by the inhibitors of CBS and CSE. Pre-treatment of myometrium strips with glibenclamide, an inhibitor of ATP-sensitive potassium (K_ATP) channels, abolished the inhibitory effect of L-cysteine on spontaneous contraction amplitude. The effects of L-cysteine on the amplitude of spontaneous contractions and baseline muscle tone were less potent in labouring tissues than that in nonlabouring strips.

Conclusion/Significance

H₂S generated by CSE and CBS locally exerts dual effects on the contractility of pregnant myometrium. Expression of H₂S synthetic enzymes is down-regulated during labour, suggesting that H₂S is one of the factors involved in the transition of pregnant uterus from quiescence to contractile state after onset of parturition.     

Redox chemistry and chemical biology of H2S,hydropersulfides, and derived species: Implications of their possible biological activity and utility

Hydrogen sulfide (H₂S) is an endogenously generated and putative signaling/effector molecule. Despite its numerous reported functions, the chemistry by which it elicits its functions is not understood. Moreover, recent studies allude to the existence of other sulfur species besides H₂S that may play critical physiological roles. Herein, the basic chemical biology of H₂S as well as other related or derived species is discussed and reviewed. This review particularly focuses on the per- and polysulfides which are likely in equilibrium with free H₂S and which may be important biological effectors themselves.     

Endogenous production of hydrogen sulfide in isolated bovine eye

Hydrogen sulfide (H₂S) is a novel gasotransmitter with physiological and pathological functions in vascular homeostasis, cardiovascular system and central nervous system. In the present study, we determined the endogenous levels of H₂S in various tissues of the bovine eye. We also examined the basal levels of H₂S in response to donors (sodium hydrosulfide, NaHS and sodium sulfide, Na₂S), substrate (l-cysteine), inhibitors (propargylglycine, PAG and aminooxyacetic acid, AOA) and activator (S-adenosyl-l-methionine, SAM) of this gas in the bovine retina. H₂S was measured using a well established spectrophotometric method. The highest concentration of endogenous H₂S was detected in cornea (19 ± 2.85 nmoles/mg protein, n = 6) and retina (17 ± 2.1 nmoles/mg protein, n = 6). Interestingly, H₂S was not present in vitreous humor. The inhibitors of CSE and CBS; PAG (1 mM) and AOA (1 mM), significantly attenuated the production of H₂S in the bovine retina by 56.8 and 42%, respectively. On the other hand the activator of CBS; SAM (100 μM), H₂S donors; NaHS (1 μM) and Na₂S (100 μM), significantly increased endogenous levels of H₂S in bovine retina. l-cysteine (10–300 μM) produced a significant (P < 0.05) concentration-dependent increase in H₂S levels reaching a maximal at 300 μM. We conclude that H₂S is endogenously produced in various tissues of the isolated bovine eye. Moreover, endogenous levels of H₂S are enhanced in the presence of substrate (l-cysteine), an activator of CBS (SAM) and H₂S donors but are blocked by inhibitors of enzymes that synthesize this gas in neural retina.     

Crosstalk between hydrogen sulfide and nitric oxide in endothelial cells

Hydrogen sulfide (H₂S) and nitric oxide (NO) are major gasotransmitters produced in endothelial cells (ECs), contributing to the regulation of vascular contractility and structural integrity. Their interaction at different levels would have a profound impact on angiogenesis. Here, we showed that H₂S and NO stimulated the formation of new microvessels. Incubation of human umbilical vein endothelial cells (HUVECs‐926) with NaHS (a H₂S donor) stimulated the phosphorylation of endothelial NO synthase (eNOS) and enhanced NO production. H₂S had little effect on eNOS protein expression in ECs. L‐cysteine, a precursor of H₂S, stimulated NO production whereas blockage of the activity of H₂S‐generating enzyme, cystathionine gamma‐lyase (CSE), inhibited this action. CSE knockdown inhibited, but CSE overexpression increased, NO production as well as EC proliferation. LY294002 (Akt/PI3‐K inhibitor) or SB203580 (p38 MAPK inhibitor) abolished the effects of H₂S on eNOS phosphorylation, NO production, cell proliferation and tube formation. Blockade of NO production by eNOS‐specific siRNA or nitro‐L‐arginine methyl ester (L‐NAME) reversed, but eNOS overexpression potentiated, the proliferative effect of H₂S on ECs. Our results suggest that H₂S stimulates the phosphorylation of eNOS through a p38 MAPK and Akt‐dependent pathway, thus increasing NO production in ECs and vascular tissues and contributing to H₂S‐induced angiogenesis.     

Endogenous hydrogen sulfide reduces airway inflammation and remodeling in a rat model of asthma

Endogenous hydrogen sulfide (H₂S) is hypothesized to have an important role in systemic inflammation. We investigated if endogenous H₂S may be a crucial mediator in airway inflammation and airway remodeling in a rat model of asthma and if endogenous H₂S may exert its anti-inflammatory effect by inhibiting inducible nitric oxide synthase (iNOS)/NO pathway. Cystathionine-γ-lyase (CSE; a H₂S-synthesizing enzyme) was mainly expressed in airway and vascular smooth muscle cells in rat lung tissue. Levels of endogenous H₂S was decreased in pulmonary tissue in ovalbumin (OVA)-treated rats. Exogenous administration of NaHS alleviated airway inflammation and airway remodeling: peak expiratory flow (PEF) increased, goblet cell hyperplasia and collagen deposition score decreased, with decreased total cells recovered from bronchoalveolar fluid (BALF) and influx of eosinophils and neutrophils. The H₂S levels of serum and lung tissue were positively correlated with PEF and negatively correlated with the level of eosinophils and neutrophils in BALF, score of lung pathology. NaHS treatment significantly attenuated pulmonary iNOS activation in OVA-treated rats. These results suggest that the CSE/H₂S pathway plays an anti-inflammatory and anti-remodeling part in asthma pathogenesis and could be a novel target in prevention and treatment of asthma.     

Physiological and pharmacological features of the novel gasotransmitter: Hydrogen sulfide

Hydrogen sulfide (H₂S) has been known for hundreds of years because of its poisoning effect. Once the basal bio-production became evident its pathophysiological role started to be investigated in depth. H₂S is a gas that can be formed by the action of two enzymes, cystathionine gamma-lyase and cystathionine beta-synthase, both involved in the metabolism of cysteine. It has several features in common with the other two well known “gasotransmitters” (nitric oxide and carbon monoxide) in the biological systems. These three gasses share some biological targets; however, they also have dissimilarities. For instance, the three gases target heme-proteins and open K_ATP channels; H₂S as NO is an antioxidant, but in contrast to the latter molecule, H₂S does not directly form radicals. In the last years H₂S has been implicated in several physiological and pathophysiological processes such as long term synaptic potentiation, vasorelaxation, pro- and anti-inflammatory conditions, cardiac inotropism regulation, cardioprotection, and several other physiological mechanisms. We will focus on the biological role of H₂S as a molecule able to trigger cell signaling. Our attention will be particularly devoted on the effects in cardiovascular system and in cardioprotection. We will also provide available information on H₂S-donating drugs which have so far been tested in order to conjugate the beneficial effect of H₂S with other pharmaceutical properties.     

H2S generated by heart in rat and its effects on cardiac function

Hydrogen sulfide (H2S), which was considered as a novel gasotransmitter, is produced endogenously from L-cysteine in mammalian brain and vessels, and might be a physiological function regulator to these organs. Here, we showed that mRNA for H2S producing enzyme, cystathionine gamma-lyase, was expressed in myocardial tissues and H2S could endogenously be produced in myocardial tissues. Negative inotropic effect of H2S was proved in present study in vitro and in vivo experiments, and the effect could partly be blocked by glibenclamide, a KATP channel blocker. An intravenous bolus injection of NaHS provoked a decrease in central venous pressure. The present findings suggested that H2S could be endogenously produced by heart tissues, as a physiological cardiac function regulator, mediated by KATP channel pathway.     

Hydrogen sulfide inhibits myocardial injury induced by homocysteine in rats

Hyperhomocysteinemia (HHcy) is a critical independent risk factor for cardiovascular diseases. However, to date, no satisfactory strategies to prevent HHcy exist. Since homocysteine (Hcy) and endogenous H₂S are both metabolites of sulfur-containing amino acids, we aimed to investigate whether a metabolic product of Hcy and H₂S, may antagonize in part the cardiovascular effects of Hcy. In the HHcy rat model injected subcutaneously with Hcy for 3 weeks, H₂S levels and the H₂S-generating enzyme cystathionine γ lyase (CSE) activity in the myocardium were decreased. The intraperitoneal injection of H₂S gas saturation solution significantly reduced plasma total Hcy (tHcy) concentration and decreased lipid peroxidation formation (i.e., lowered manodialdehyde and conjugated diene levels in myocardia and plasma). The activities of myocardial mitochondrial respiratory enzymes succinate dehydrogenase, cytochrome oxidase, and manganese superoxide dismutase, related to reactive oxygen species metabolism, were significantly dysfunctional in HHcy rats. The H₂S administration restored the level of enzyme activities and accelerated the scavenging of H₂O₂ and superoxide anion generated by Hcy in isolated mitochondria. The H₂S treatment also inhibited the expression of glucose-regulated protein 78, a marker of endoplasmic reticulum (ER) stress, induced by Hcy in vivo and in vitro. Thus, HHcy impaired the myocardial CSE/H₂S pathway, and the administration of H₂S protected the myocardium from oxidative and ER stress induced by HHcy, which suggests that an endogenous metabolic balance of sulfur-containing amino acids may be a novel strategy for treatment of HHcy.     

Endogenous hydrogen sulfide regulation of myocardial injury induced by isoproterenol

Previous work has shown that the endogenous cystathionine γ-synthase (CSE)/hydrogen sulfide (H₂S) pathway participates in the regulation of cardiac contraction. We hypothesized that the pathway might participate in the pathophysiological regulation of ischemic heart disease. Isoproterenol injection of rat hearts induced a myocardial ischemic injury model, with reduced myocardial and plasma H₂S levels, decreased CSE activity, and upregulated CSE gene expression. Exogenous administration of the H₂S donor NaHS reduced the mortality rate; increased left-ventricular pressure development and left-ventricular-end systolic pressure; and decreased left-ventricular-end diastolic pressure (LVEDP) and subendocardial necrosis, capillary dilatation, leukocytic infiltration, fibroblast swelling, and fibroblastic hyperplasia. As well, production of lipid peroxidation, including myocardial malondialdehyde (MDA), and plasma MDA and conjugated diene, was reduced. Oxidative stress injury is an important mechanism of isoproterenol-induced myocardial injury. In vitro experiments revealed that NaHS might antagonize myocyte MDA production by oxygen-free radicals and that NaHS directly scavenged hydrogen peroxide and superoxide anions. Our results suggest that the endogenous CSE/H₂S pathway contributes to the pathogenesis of isoproterenol-induced myocardial injury. Administration of exogenous H₂S effectively protects myocytes and contractile activity, at least by its direct scavenging of oxygen-free radicals and reducing the accumulation of lipid peroxidations.     

Nongenomic signaling pathways triggered by thyroid hormones and their metabolite 3‐iodothyronamine on the cardiovascular system

Thyroid hormones play a wide range of important physiological activities in almost all organism. As changes in these hormones levels—observed in hypothyroidism and hyperthyroidism—promote serious derangements of the cardiovascular system, it is important to know their mechanisms of action. Although the classic genomic actions which are dependent on interaction with nuclear receptors to modulate cardiac myocytes genes expression, there is growing evidence about T₃ and T₄‐triggered nongenomic pathways, resulted from their binding to plasma membrane, cytoplasm, or mitocondrial receptors that leads to a rapidly regulation of cardiac functions. Interestingly both actions converge to amplify thyroid hormone effects on cardiovascular system. T₃ and T₄ nongenomic actions modify inotropic and chronotropic effects, cardiac action potential duration, cardiac growth, and myocyte shape by protein translation through protein kinases‐dependent signaling cascades, which include PKA, PKC, PI3K, and MAPK, and changes on ion channels and pumps activity. In respect to the decreased systemic vascular resistance seen in hyperthyroidism, T₃ appears to activate NOS or ATP‐sensitive K⁺ channels. In addition, a novel biologically active T₄‐derived metabolite has been described, 3‐iodothyronamine, T₁AM, which also acts through membrane receptors to mediate nongenomic cardiac effects. This metabolite influences the physiological manifestations of thyroid hormone actions by inducing opposite effects from those stimulated by T₃ and T₄, such as negative inotropic and chronotropic effects. Therefore, beyond genomic and nongenomic effects of thyroid hormones, it is crucial for there to be an equilibrium between T₃ or T₄ and T₁AM levels for maintaining cardiac homeostasis. J. Cell. Physiol. 226: 21–28, 2010. © 2010 Wiley‐Liss, Inc.     

The conversion of leukotriene C4 to isomers of leukotriene B4 by human eosinophil peroxidase

The smooth muscle contractile and vasoactive mediator leukotriene C₄ (5(S)-hydroxy-6(R)-sulfido-glutathionyl-eicosatetraenoic acid; LTC₄) is converted by phorbol ester-stimulated human eosinophils to two isomers of leukotriene B₄, 5(S),12(R)-6,8,10 trans-14 cis-eicosatetraenoic acid (5(S),12(R)-“all-trans”-LTB₄) and 5(S),12(S)-“all-trans”-LTB₄, which are leukocyte chemotactic factors lacking the humoral functions of LTC₄. Optimal conversion of LTC₄ to the “all-trans” isomers of LTB₄ by intact eosinophils and soluble eosinophil peroxidase requires both H₂O₂ and halide ions. Oxidative metabolism of leukotrienes may represent an important regulatory function of eosinophils in hypersensitivity reactions.