Roles of Hydrogen Sulfide in the Pathogenesis of Diabetes Mellitus and Its Complications

Szabó, Csaba

doi:10.1089/ars.2011.4451

Cited by 196 publications

(150 citation statements)

References 80 publications

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“…7C). Finally, given that H 2 S plays multiple protective roles in both the vasculature and the heart, it can be suggested that lower circulating and tissue H 2 S levels may contribute to the pathophysiology of diabetes (28) and strategies aimed at correcting this decline may serve as an effective therapeutic option in the treatment of heart disease in the setting of diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, additional studies found that STZ does not alter the expression of either enzyme in the aorta, liver, kidney, or heart (4,27). Despite this contrasting evidence about the effects of STZ-induced diabetes on the expression of CSE and CBS, there is clear evidence that circulating levels of H 2 S are decreased in animal models of diabetes (12,27,37) and may even contribute to the pathophysiology of diabetes (28). More importantly, lower circulating H 2 S levels have been detected in plasma samples taken from patients with type 2 diabetes mellitus (T2DM) (12,32).…”

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confidence: 97%

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Hydrogen sulfide preconditions thedb/dbdiabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner

Peake

Nicholson

Lambert

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

150

121

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Hydrogen sulfide preconditions the db/db diabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner. Am J Physiol Heart Circ Physiol 304: H1215-H1224, 2013. First published March 11, 2013 doi:10.1152/ajpheart.00796.2012.-Hydrogen sulfide (H2S) therapy protects nondiabetic animals in various models of myocardial injury, including acute myocardial infarction and heart failure. Here, we sought to examine whether H2S therapy provides cardioprotection in the setting of type 2 diabetes. H2S therapy in the form of sodium sulfide (Na2S) beginning 24 h or 7 days before myocardial ischemia significantly decreased myocardial injury in db/db diabetic mice (12 wk of age). In an effort to evaluate the signaling mechanism responsible for the observed cardioprotection, we focused on the role of nuclear factor E2-related factor (Nrf2) signaling. Our results indicate that diabetes does not alter the ability of H2S to increase the nuclear localization of Nrf2, but does impair aspects of Nrf2 signaling. Specifically, the expression of NADPH quinine oxidoreductase 1 was increased after the acute treatment, whereas the expression of hemeoxygenase-1 (HO-1) was only increased after 7 days of treatment. This discrepancy was found to be the result of an increased nuclear expression of Bach1, a known repressor of HO-1 transcription, which blocked the binding of Nrf2 to the HO-1 promoter. Further analysis revealed that 7 days of Na2S treatment overcame this impairment by removing Bach1 from the nucleus in an Erk1/2-dependent manner. Our findings demonstrate for the first time that exogenous administration of Na2S attenuates myocardial ischemia-reperfusion injury in db/db mice, suggesting the potential therapeutic effects of H2S in treating a heart attack in the setting of type 2 diabetes. hydrogen sulfide; type 2 diabetes; myocardial infarction; nuclear factor E2-related factor

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

Hydrogen sulfide preconditions thedb/dbdiabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner

Peake

Nicholson

Lambert

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

150

121

View full text Add to dashboard Cite

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“…This indicates that the signaling and effector pathways downstream from H 2 S are not impaired significantly in experimental models used in the current study. It must be noted that, depending on the experimental conditions and models used, the other H 2 S-producing enzyme systems also have been shown to be affected by diabetes and diabetic complications (8)(9)(10)(11)(12)(13)(14)(15)(65)(66)(67); overviewed in [67]). Thus, it is likely that there is a complex dysregulation of the H 2 S system in diabetes, the nature of which depends on the model used, as well as the stage and severity of the disease.…”

Section: M P a I R M E N T O F T H E 3 -M S T / H 2 S P A T H W A Ymentioning

confidence: 99%

Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by dl-α-Lipoic Acid

Coletta

Módis

Szczesny

et al. 2015

Mol Med

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126

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Hydrogen sulfide (H 2 S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H 2 S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H 2 S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H 2 S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H 2 S levels in rats. 3-MP (10 μmol/L to 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3-1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H 2 S production depended on enzymatic activity, although at higher concentrations (1-3 mmol/L) there was also evidence for an additional nonenzymatic H 2 S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants DL-α-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H 2 S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H 2 S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and bioenergetics in hyperglycemia.

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“…Experimental evidences have been published implicating H 2 S overproduction as a causative factor in the pathogenesis of β-cell death in diabetes. 12,13 Some other experiments have suggested H 2 S deficiency due to increased H 2 S consumption by hyperglycemic cells, in the pathogenesis of diabetic endothelial dysfunction, diabetic nephropathy, and cardiomyopathy. 12 There is possibility that the modulation of H 2 S production may be a potential therapeutic strategy for diabetes mellitus.…”

Section: Enhanced Plasma H 2 S Levels Associated With Fasting Blood Gmentioning

confidence: 99%

“…12,13 Some other experiments have suggested H 2 S deficiency due to increased H 2 S consumption by hyperglycemic cells, in the pathogenesis of diabetic endothelial dysfunction, diabetic nephropathy, and cardiomyopathy. 12 There is possibility that the modulation of H 2 S production may be a potential therapeutic strategy for diabetes mellitus. 13 This has led researchers to investigate H 2 S related substances for treatment of diabetes.…”

Section: Enhanced Plasma H 2 S Levels Associated With Fasting Blood Gmentioning

confidence: 99%

Enhanced Plasma H2S Levels Associated With Fasting Blood Glucose In Type-2 Diabetes Mellitus

et al. 2015

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Introduction: A number of recent literatures suggest a potential role of H 2 S and H 2 S modifying agents in the etiology and management of type-2 diabetes mellitus. Objective: The current study was aimed to evaluate the plasma levels of H 2 S in the patients with type 2 Diabetes mellitus and to find out if there is any relationship of H 2 S concentrations with the fasting blood glucose levels. Methods: Plasma H 2 S levels were measured in sixty two recently diagnosed type 2 diabetic patients and compared with similar number of healthy volunteers as controls. Results: The plasma H 2 S level in the patients (81.17 ± 16.40 micromol/l) is significantly higher (P< 0.001) than the healthy controls (50.69 ± 8.69 micromol/l) and the H 2 S levels in plasma have significant positive correlation (r= 0.359, P=0.004) with fasting blood glucose levels. Conclusion: The present study has elucidated that the patients with type-2 diabetes mellitus are associated with elevated plasma H 2 S levels which are well correlated with glucose levels. This reveals a potential role of H 2 S modulators towards the management of this non-communicable epidemic disorder.

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Roles of Hydrogen Sulfide in the Pathogenesis of Diabetes Mellitus and Its Complications

Abstract: In the final section of the review, future research directions and potential experimental therapeutic approaches around the pharmacological modulation of H(2)S homeostasis in diabetes are discussed.

Cited by 196 publications

References 80 publications

Hydrogen sulfide preconditions thedb/dbdiabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner

Hydrogen sulfide preconditions thedb/dbdiabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner

Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by dl-α-Lipoic Acid

Enhanced Plasma H2S Levels Associated With Fasting Blood Glucose In Type-2 Diabetes Mellitus

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