Cardioprotective Role of Sodium Thiosulfate on Chronic Heart Failure by Modulating Endogenous H&lt;sub&gt;2&lt;/sub&gt;S Generation

Sen, Utpal; Vacek, Thomas P.; Hughes, William F.; Kumar, Munish; Moshal, Karni S.; Tyagi, Neetu; Metreveli, Naira; Hayden, Melvin R.; Tyagi, Suresh C.

doi:10.1159/000156486

Cited by 68 publications

(71 citation statements)

References 79 publications

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“…S-adenosylmethionine and pyridoxal-5′-phosphate stimulate CSE activity to increase H 2 S production (69,70). Alternatively to increasing CSE expression as a therapeutic option, rescue may be provoked by STS because our data show a protective effect of this compound as well, and it is tolerated by humans in high concentrations (71,72).…”

Section: Discussionmentioning

confidence: 89%

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Snijder

Baratashvili

Grzeschik

et al. 2015

Mol Med

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Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ataxin-3 (ATXN3) gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative disease. There is no cure that halts or reverses the progressive neurodegeneration of SCA3. Here we show that overexpression of cystathionine γ-lyase, a central enzyme in cysteine metabolism, is protective in a Drosophila model for SCA3. SCA3 flies show eye degeneration, increased oxidative stress, insoluble protein aggregates, reduced levels of protein persulfidation and increased activation of the innate immune response. Overexpression of Drosophila cystathionine γ-lyase restores protein persulfidation, decreases oxidative stress, dampens the immune response and improves SCA3-associated tissue degeneration. Levels of insoluble protein aggregates are not altered; therefore, the data implicate a modifying role of cystathionine γ-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine γ-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine γ-lyase expression or activity are attractive candidates for future therapies.

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Section: Discussionmentioning

confidence: 89%

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Snijder

Baratashvili

Grzeschik

et al. 2015

Mol Med

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“…Blood (0.5 ml) was collected, and plasma was separated from each mice. The plasma levels of H2S were estimated by colorimetric titration as previously described (20). The sulfide measurement was a critical, and very tricky, parameter to measure.…”

Section: Methodsmentioning

confidence: 99%

“…The H 2S values could be inflated as an artifact of the technique. Nonetheless, we (20) previously measured sulfide production from left ventricle (LV) homogenates. We adapted a similar method to measure the plasma levels of H 2S.…”

Section: Methodsmentioning

confidence: 99%

H₂S ameliorates oxidative and proteolytic stresses and protects the heart against adverse remodeling in chronic heart failure

Mishra

Tyagi

Sen

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Mishra PK, Tyagi N, Sen U, Givvimani S, Tyagi SC. H2S ameliorates oxidative and proteolytic stresses and protects the heart against adverse remodeling in chronic heart failure. Am J Physiol Heart Circ Physiol 298: H451-H456, 2010. First published November 20, 2009; doi:10.1152/ajpheart.00682.2009.-Reactive oxygen and nitrogen species (ROS and RNS, respectively) generate nitrotyrosine and activate latent resident myocardial matrix metalloproteinases (MMPs). Although in chronic heart failure (CHF) there is robust increase in ROS, RNS, and MMP activation, recent data suggest that hydrogen sulfide (H 2S, a strong antioxidant gas) is cardioprotective. However, the role of H 2S in mitigating oxidative and proteolytic stresses in cardiac remodeling/apoptosis in CHF was unclear. To test the hypothesis that H 2S ameliorated cardiac apoptosis and fibrosis by decreasing oxidative and proteolytic stresses, arteriovenous fistula (AVF) was created in wild-type (C57BL/6J) mice. The hearts were analyzed at 0, 2, and 6 wk after AVF. To reverse the remodeling, AVF mice were treated with NaHS (an H 2S donor, 30 mol/l in drinking water) at 8 and 10 wk. The levels of MMPs were measured by gelatin-gel zymography. The levels of nitrotyrosine, tissue inhibitors of metalloproteinase (TIMPs), ␤ 1-integrin, and a disintegrin and metalloproteinase-12 (ADAM-12) were analyzed by Western blots. The levels of pericapillary and interstitial fibrosis were identified by Masson trichrome stains. The levels of apoptosis were measured by identifying the TdT-mediated dUTP nick end labeling (TUNEL)-positive cells and caspase-3 levels. The results suggested robust nitrotyrosine and MMP activation at 2 and 6 wk of AVF. The treatment with H 2S donor mitigated nitrotyrosine generation and MMP activation (i.e., oxidative and proteolytic stresses). The levels of TIMP-1 and TIMP-3 were increased and TIMP-4 decreased in AVF hearts. The treatment with H 2S donor reversed this change in TIMPs levels. The levels of ADAM-12, apoptosis, and fibrosis were robust and integrin were decreased in AVF hearts. The treatment with H 2S donor attenuated the fibrosis, apoptosis, and decrease in integrin. fibrosis; extracellular matrix; ADAM; integrin; matrix metalloproteinase; tissue inhibitor of metalloproteinase; left ventricle hypertrophy; collagen; TUNEL; apoptosis; homocysteine ALTHOUGH IN GASTROINTESTINAL and nervous systems hydrogen sulfide (H 2 S) plays a crucial role as a signaling molecule (12, 24), recent studies established that H 2 S is a cardioprotective gas (4, 21, 27). However, its role in regulating the ECM remodeling and apoptosis is still nebulous. Considering the tremendous therapeutic potential, H 2 S gas has attracted the attention of biomedical research (2,5,9,10,12). It is a strong antioxidant and is generated endogenously by two important enzymes involved in sulfur-containing amino acid [cysteine and homocysteine (Hcy)] metabolism, namely cystathionine ␤-synthase (CBS) and cystathionine ␥-lyase (CGL) (26). Paradoxically, it is interesting that hyperh...

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“…Thiosulfate is an endogenous product from the oxidative metabolism of hydrogen sulphide in mitochondria is reported as not only a reducing and antioxidant agent involved in scavenging ROS but also can activate the gene expression of antioxidant enzymes [31] . Recently, its cardioprotective effect was documented through its ability to release hydrogen sulfide in the mitochondria [12] . CoCl 2 is effective in inducing ROS via mitochondria [32] and our results with STS on this model demonstrate that the drug has the potential to scavenge ROS effectively, when it was given along with cobalt chloride.…”

Section: Resultsmentioning

confidence: 99%

“…It is a general belief that mitochondrial toxicity depends on the production of free radicals. In the present study, we evaluate the mitochondrial protective effect of sodium thiosulfate (STS), a FDA approved drug for cyanide toxicity [10] , calciphylaxis [11] , found to be cardioprotective [12] , reduce free radical release and could act as a calcium ion chelator [13] .…”

mentioning

confidence: 99%

Effect of Sodium Thiosulfate on Isolated Cardiac Interfibrillar and Subsarcolemmal Mitochondria

Banu¹,

Shifana²,

Fathima³

et al. 2016

IJPS

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Shakila Banu, et al.: Effect of Sodium Thiosulfate on Isolated Cardiac MitochondriaMitochondria are the key players of cardiac function and their dysfunction due to oxidative stress is implicated in myocardial ischemia reperfusion injury, one of the important mediators of cardiac mortality. The present study evaluates the mitochondrial protective effect of sodium thiosulfate on isolated cardiac mitochondria (interfibrillar mitochondria and subsarcolemmal mitochondria) subjected to oxidative stress by ischemia and reperfusion. Briefly, interfibrillar mitochondria and subsarcolemmal mitochondria were treated with cobalt chloride (500 µM) for 20 min to induce oxidative stress by chemical method and nitrogen gas purging for 20 min in an ischemic buffer was used for the physiological method. The mitoprotective effect of sodium thiosulfate was evaluated with different mode of sodium thiosulfate incubation (pretreatment, cotreatment and post treatment) with the mitochondria. The mitochondria led to an increased oxidative stress (measured by malondialdehyde, reduced glutathione, superoxide dismutase and glutathione peroxidase) and decreased mitochondrial enzyme activities (measured by succinate dehydrogenase, malate dehydrogenase and NAD+ dehydrogenase) with both the models and sodium thiosulfate treated groups showed significant improvement in the above alterations. By comparing the efficiency among the different modes of sodium thiosulfate treatment, we found that pretreatment renders significant (P<0.05) mitochondrial protection against ischemia reperfusion injury by nitrogen gas. However, no such differences were observed among the treatments in cobalt chloride mediated mitochondrial dysfunction. In summary, we found that sodium thiosulfate can modulate and preserve cardiac mitochondria for the treatment of myocardial ischemia reperfusion injury.Key words: Interfibrillar mitochondria (IFM), subsarcolemmal mitochondria (SSM), oxidative stress, sodium thiosulfate, mitochondrial dysfunctionMitochondrial dysfunction leads to a wide range of cardiac pathologies including myocardial ischemia reperfusion, because of its primary role in heart metabolism with respect to energy production, metabolism and homeostasis. Incidentally, the majority of intracellular reactive oxygen species (ROS, superoxide, hydroxide and hydrogen peroxide) that mediate the oxidative stress, are derived from mitochondria via electron transport chain (ETC), especially complex I and complex III redox sites [1][2][3] . Ischemia reperfusion (I/R) injury, a major contributor to the damage encountered during myocardial infarction is experimentally studied by performing microsurgery on rodents; isolated heart perfusion with Langendorff setup and by mimicking it in cell lines utilizing anaerobic chamber. All these approaches have their own benefits with certain limitations and thus the translation of the preclinical results from these models is not very encouraging. Considering the significant role of mitochondria in determining the pathology of I/R injury ...

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Cardioprotective Role of Sodium Thiosulfate on Chronic Heart Failure by Modulating Endogenous H<sub>2</sub>S Generation

Cited by 68 publications

References 79 publications

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

H₂S ameliorates oxidative and proteolytic stresses and protects the heart against adverse remodeling in chronic heart failure

Effect of Sodium Thiosulfate on Isolated Cardiac Interfibrillar and Subsarcolemmal Mitochondria

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