Hydrogen Sulfide: A Potential Novel Therapy for the Treatment of Ischemia

Jensen, Amanda R.; Drucker, Natalie A.; Khaneki, Sina; Ferkowicz, Michael J.; Yoder, Mervin C.; DeLeon, Eric R.; Olson, Kenneth R.; Markel, Troy A.

doi:10.1097/shk.0000000000000894

Cited by 17 publications

(6 citation statements)

References 133 publications

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“…Our data indicate that RHY-1 has novel, hif-1 independent, function that promotes survival in H 2 S. KEYWORDS C. elegans; hif-1; hydrogen sulfide; rhy-1; skn-1, WormBase H ydrogen sulfide (H 2 S) is produced endogenously by animal cells, and has various roles in cellular signaling (Li et al 2011). Exposure to relatively low levels of exogenous H 2 S induces a suspended-animation like state in rodents that is associated with increased survival in whole-body hypoxia, and improved outcome in models of ischemia-reperfusion injury (Blackstone and Roth 2007;Wu et al 2015;Jensen et al 2017). In Caenorhabditis elegans, exogenous H 2 S increases lifespan and protects from hypoxia-induced protein aggregation (Miller and Roth 2007;Fawcett et al 2015), suggesting that protective effects of H 2 S may be conserved.…”

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confidence: 99%

A Novel Mechanism To Prevent H2S Toxicity in Caenorhabditis elegans

Horsman¹,

Heinis²,

Miller

2019

Genetics

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Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that can be cytoprotective, especially in conditions of ischemia/reperfusion injury. However, H2S is also toxic, and unregulated accumulation or exposure to environmental H2S can be lethal. In Caenorhabditis elegans, the hypoxia inducible factor (hif-1) coordinates the initial transcriptional response to H2S, and is essential to survive exposure to low concentrations of H2S. We performed a forward genetic screen to identify mutations that suppress the lethality of hif-1 mutant animals in H2S. The mutations we recovered are specific for H2S, as they do not suppress embryonic lethality or reproductive arrest of hif-1 mutant animals in hypoxia, nor can they prevent the death of hif-1 mutant animals exposed to hydrogen cyanide. The majority of hif-1 suppressor mutations we recovered activate the skn-1/Nrf2 transcription factor. Activation of SKN-1 by hif-1 suppressor mutations increased the expression of a subset of H2S-responsive genes, consistent with previous findings that skn-1 plays a role in the transcriptional response to H2S. Using transgenic rescue, we show that overexpression of a single gene, rhy-1, is sufficient to protect hif-1 mutant animals in H2S. The rhy-1 gene encodes a predicated O-acyltransferase enzyme that has previously been shown to negatively regulate HIF-1 activity. Our data indicate that RHY-1 has novel, hif-1 independent, function that promotes survival in H2S.

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confidence: 99%

A Novel Mechanism To Prevent H2S Toxicity in Caenorhabditis elegans

Horsman¹,

Heinis²,

Miller

2019

Genetics

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“…Under hypoxic conditions, H 2 S plays a key protective role against ischemia/reperfusion damages [54, 55] through only partly understood molecular mechanisms including induction of antioxidant and vasorelaxation effects on microcirculation. Moreover, H 2 S appears to mediate the repair of damaged mitochondrial DNA [36], occurring in ischemia/reperfusion, and to protect from hypoxia-induced proteostasis disruption, as demonstrated in Caenorhabditis elegans [65].…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia is thus expected to increase H 2 S bioavailability, a condition that can have opposite physiological consequences. Indeed, while H 2 S has been shown to be protective against ischemic injuries [54, 55], the enhanced biosynthesis and chemical stability of H 2 S, combined with the reduced content in mitochondria (the main sites of sulfide disposal), may increase the risk of H 2 S toxicity in hypoxic cells.…”

Section: Introductionmentioning

confidence: 99%

Hydrogen Sulfide Oxidation: Adaptive Changes in Mitochondria of SW480 Colorectal Cancer Cells upon Exposure to Hypoxia

Malagrinò

Zuhra

Mascolo

et al. 2019

Oxidative Medicine and Cellular Longevity

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Hydrogen sulfide (H2S), a known inhibitor of cytochrome c oxidase (CcOX), plays a key signaling role in human (patho)physiology. H2S is synthesized endogenously and mainly metabolized by a mitochondrial sulfide-oxidizing pathway including sulfide:quinone oxidoreductase (SQR), whereby H2S-derived electrons are injected into the respiratory chain stimulating O2 consumption and ATP synthesis. Under hypoxic conditions, H2S has higher stability and is synthesized at higher levels with protective effects for the cell. Herein, working on SW480 colon cancer cells, we evaluated the effect of hypoxia on the ability of cells to metabolize H2S. The sulfide-oxidizing activity was assessed by high-resolution respirometry, measuring the stimulatory effect of sulfide on rotenone-inhibited cell respiration in the absence or presence of antimycin A. Compared to cells grown under normoxic conditions (air O2), cells exposed for 24 h to hypoxia (1% O2) displayed a 1.3-fold reduction in maximal sulfide-oxidizing activity and 2.7-fold lower basal O2 respiration. Based on citrate synthase activity assays, mitochondria of hypoxia-treated cells were 1.8-fold less abundant and displayed 1.4-fold higher maximal sulfide-oxidizing activity and 2.6-fold enrichment in SQR as evaluated by immunoblotting. We speculate that under hypoxic conditions mitochondria undergo these adaptive changes to protect cell respiration from H2S poisoning.

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“…Pathophysiological consequences of the H 2 S/O 2 axis. Additional details can be found in a number of recent reviews [ 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 ].…”

Section: Evidence For H 2 S Mediated O 2 Sensing In Various Organ Systems and Tissuesmentioning

confidence: 99%

A Case for Hydrogen Sulfide Metabolism as an Oxygen Sensing Mechanism

Olson

2021

Antioxidants

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The ability to detect oxygen availability is a ubiquitous attribute of aerobic organisms. However, the mechanism(s) that transduce oxygen concentration or availability into appropriate physiological responses is less clear and often controversial. This review will make the case for oxygen-dependent metabolism of hydrogen sulfide (H2S) and polysulfides, collectively referred to as reactive sulfur species (RSS) as a physiologically relevant O2 sensing mechanism. This hypothesis is based on observations that H2S and RSS metabolism is inversely correlated with O2 tension, exogenous H2S elicits physiological responses identical to those produced by hypoxia, factors that affect H2S production or catabolism also affect tissue responses to hypoxia, and that RSS efficiently regulate downstream effectors of the hypoxic response in a manner consistent with a decrease in O2. H2S-mediated O2 sensing is then compared to the more generally accepted reactive oxygen species (ROS) mediated O2 sensing mechanism and a number of reasons are offered to resolve some of the confusion between the two.

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Hydrogen Sulfide: A Potential Novel Therapy for the Treatment of Ischemia

Cited by 17 publications

References 133 publications

A Novel Mechanism To Prevent H2S Toxicity in Caenorhabditis elegans

A Novel Mechanism To Prevent H2S Toxicity in Caenorhabditis elegans

Hydrogen Sulfide Oxidation: Adaptive Changes in Mitochondria of SW480 Colorectal Cancer Cells upon Exposure to Hypoxia

A Case for Hydrogen Sulfide Metabolism as an Oxygen Sensing Mechanism

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