H<sub>2</sub>S Is an Endothelium-Derived Hyperpolarizing Factor

Tang, Guanghua; Yang, Guangdong; Jiang, Bo; Ju, Youngjun; Wu, Lingyun; Wang, Rui

doi:10.1089/ars.2012.4805

Cited by 119 publications

(107 citation statements)

References 49 publications

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“…Cystathionine beta-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3MST) also have been reported to contribute to the endogenous generation of H 2 S in vascular cells (34,35). The effects of H 2 S in the vascular system are complex and permit H 2 S to exert a wide range of actions, including vasodilatation, angiogenesis, cellular bioenergetics, and energy production (13,38,39). The signaling mechanisms underlying the multifaceted vascular effects of H 2 S have been attributed to activating K ATP channels, inducing cell membrane hyperpolarization, increasing intracellular calcium, altering cellular cGMP and cAMP levels, attenuating inflammation and oxidative stress, and so on (4,26,43).…”

Section: Introductionmentioning

confidence: 99%

Hydrogen Sulfide Maintains Mitochondrial DNA Replication via Demethylation of TFAM

Yang

2015

Antioxidants & Redox Signaling

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Aims: Hydrogen sulfide (H 2 S) exerts a wide range of actions in the body, especially in the modulation of mitochondrial functions. The normal replication of mitochondrial DNA (mtDNA) is critical for cellular energy metabolism and mitochondrial biogenesis. The aim of this study was to investigate whether H 2 S affects mtDNA replication and the underlying mechanisms. We hypothesize that H 2 S maintains mtDNA copy number via inhibition of Dnmt3a transcription and TFAM promoter methylation. Results: Here, we demonstrated that deficiency of cystathionine gamma-lyase (CSE), a major H 2 S-producing enzyme, reduces mtDNA copy number and mitochondrial contents, and it inhibits the expressions of mitochondrial transcription factor A (TFAM) and mitochondrial marker genes in both smooth muscle cells and aorta tissues from mice. Supply of exogenous H 2 S stimulated mtDNA copy number and strengthened the expressions of TFAM and mitochondrial marker genes. TFAM knockdown diminished H 2 S-enhanced mtDNA copy number. In addition, CSE deficiency induced the expression of DNA methyltransferase 3a (Dnmt3a) and TFAM promoter DNA methylation, and H 2 S repressed Dnmt3a expression, resulting in TFAM promoter demethylation. We further found that H 2 S S-sulfhydrates transcription repressor interferon regulatory factor 1 (IRF-1) and enhances the binding of IRF-1 with Dnmt3a promoter after reduced Dnmt3a transcription. H 2 S had little effects on the expression of Dnmt1 and Dnmt3b as well as on ten-eleven translocation methylcytosine dioxygenase 1, 2, and 3. Innovation: A sufficient level of H 2 S is able to inhibit TFAM promoter methylation and maintain mtDNA copy number. Conclusion: CSE/H 2 S system contributes to mtDNA replication and cellular bioenergetics and provides a novel therapeutic avenue for cardiovascular diseases. Antioxid. Redox Signal. 23, 630-642.

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Section: Introductionmentioning

confidence: 99%

Hydrogen Sulfide Maintains Mitochondrial DNA Replication via Demethylation of TFAM

Yang

2015

Antioxidants & Redox Signaling

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“…Indeed, it was notable that the EC 50 for polysulfide-induced vasodilation is ≈15 μmol/L, an order of magnitude lower than that typically observed for NaSH by us and others. 3,[27][28][29] Consequently, the concentration of intracellularly generated polysulfide that would induce oxidative activation of PKG could be a lot lower than the concentration of NaSH applied exogenously. Although NaSH is a commonly used tool, for the reasons explained, the concentration applied exogenously should not in any way be considered to reflect those produced endogenously.…”

Section: 18mentioning

confidence: 99%

Protein Kinase G Iα Oxidation Paradoxically Underlies Blood Pressure Lowering by the Reductant Hydrogen Sulfide

et al. 2014

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Abstract-Dysregulated blood pressure control leading to hypertension is prevalent and is a risk factor for several common diseases. Fully understanding blood pressure regulation offers the possibility of developing rationale therapies to alleviate hypertension and associated disease risks. Although hydrogen sulfide (H 2 S) is a well-established endogenous vasodilator, the molecular basis of its blood-pressure lowering action is incompletely understood. H 2 S-dependent vasodilation and blood pressure lowering in vivo was mediated by it catalyzing formation of an activating interprotein disulfide within protein kinase G (PKG) Iα. However, this oxidative activation of PKG Iα is counterintuitive because H 2 S is a thiol-reducing molecule that breaks disulfides, and so it is not generally anticipated to induce their formation. This apparent paradox was explained by H 2 S in the presence of molecular oxygen or hydrogen peroxide rapidly converting to polysulfides, which have oxidant properties that in turn activate PKG by inducing the disulfide. These observations are relevant in vivo because transgenic knockin mice in which the cysteine 42 redox sensor within PKG has been systemically replaced with a redox-dead serine residue are resistant to H 2 S-induced blood pressure lowering. Thus, a primary mechanism by which the reductant molecule H 2 S lowers blood pressure is mediated somewhat paradoxically by the oxidative activation of PKG. (Hypertension. 2014;64:1344-1351.)

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“…An increasing number of reports show that contribution of H 2 S depends on vascular beds tested (e.g., aorta vs. mesenteric artery), vessel size (conduit vs. resistant) [5], endothelium (intact vs. denuded), gender [19], duration, concentration, and rate of administration of H 2 S or its donor (e.g., NaHS). Other factors influencing H 2 S response in the vasculature are model organisms and the preconstriction methods (e.g., phenylephrine, U46619) [20,21].…”

Section: H 2 S In the Vasculaturementioning

confidence: 99%

“…Mechanisms of H 2 S-induced vasodilation consist of several complex pathways, including regulation of various ion channels, reduction of intracellular pH in SMCs [28], increase in cAMP production [29], and increase in cGMP by inhibition of phosphodiesterase (PDE) [30]. Furthermore, H 2 S has been shown to act as an adipocyte-derived relaxing factor (ADRF) [10], and as an endothelium-derived hyperpolarizing factor (EDHF) [19]. Although the mechanisms of H 2 S-induced vasodilation need to be explored further, its known functions suggest a significant role in a number of mechanism that contribute to the development of cardiovascular disease (CVD) therefore making it an attractive clinical target.…”

Section: Introductionmentioning

confidence: 99%

H2S in the Vasculature: Controversy of Mechanisms in Physiology, Pathology and Beyond

Beyer¹

2015

Cardiol Pharmacol

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Hydrogen sulfide (H 2 S) is an endogenously gaseous messenger with a number of physiological effects. Pharmacological and genetic models point toward an important role for this vasodilator gas in the regulation of vascular tone, cardiac response to ischemia/reperfusion injury, and inflammation among others. Understanding the complex interaction of H 2 S with basic cellular signaling and its impact on endothelial and smooth muscle physiology may provide insights into the early stages of developing vascular inflammation and atherosclerosis or related vascular pathologies. The underlying mechanism of action is not completely understood. Recent evidence suggests a key role of H 2 S in protecting mitochondria against oxidative damage, regulation of ion channels and modulation of eNOS activity. This review will focus on the key role of H 2 S in the regulation of vascular function including free radical production and its physiological role in health and disease.

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H₂S Is an Endothelium-Derived Hyperpolarizing Factor

Cited by 119 publications

References 49 publications

Hydrogen Sulfide Maintains Mitochondrial DNA Replication via Demethylation of TFAM

Hydrogen Sulfide Maintains Mitochondrial DNA Replication via Demethylation of TFAM

Protein Kinase G Iα Oxidation Paradoxically Underlies Blood Pressure Lowering by the Reductant Hydrogen Sulfide

H2S in the Vasculature: Controversy of Mechanisms in Physiology, Pathology and Beyond

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H2S Is an Endothelium-Derived Hyperpolarizing Factor

Cited by 119 publications

References 49 publications

Hydrogen Sulfide Maintains Mitochondrial DNA Replication via Demethylation of TFAM

Hydrogen Sulfide Maintains Mitochondrial DNA Replication via Demethylation of TFAM

Protein Kinase G Iα Oxidation Paradoxically Underlies Blood Pressure Lowering by the Reductant Hydrogen Sulfide

H2S in the Vasculature: Controversy of Mechanisms in Physiology, Pathology and Beyond

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H₂S Is an Endothelium-Derived Hyperpolarizing Factor