The novel mitochondria-targeted hydrogen sulfide (H 2 S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro

Gerö, Domokos; Torregrossa, Roberta; Perry, Alexis; Waters, Alicia; Le-Trionnaire, Sophie; Whatmore, Jacqueline L.; Wood, Mark E.; Whiteman, Matthew

doi:10.1016/j.phrs.2016.08.019

Cited by 140 publications

(106 citation statements)

References 65 publications

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“…Hyperglycaemia leads to mitochondrial superoxide generation, which initiates endothelial dysfunction and oxidant production [32]. H 2 S serves as an electron donor to the respiratory chain and plays a therapeutic role in DM and vascular diseases [33, 34]. A recent in vitro study also showed that H 2 S inhibits Aβ-induced neuronal apoptosis by regulating mitochondrial function [35].…”

Section: Introductionmentioning

confidence: 99%

Exogenous Hydrogen Sulfide Ameliorates Diabetes-Associated Cognitive Decline by Regulating the Mitochondria-Mediated Apoptotic Pathway and IL-23/IL-17 Expression in db/db Mice

Zhong

et al. 2017

Cell Physiol Biochem

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Background: Diabetes-associated cognitive decline (DACD) is one of the complications of diabetes and leads to cognitive impairment and an increased risk of dementia. However, the exact mechanism of DACD has not been fully characterized, and a successful therapy for this issue has not been established. This study aimed to detect the anti-apoptotic and anti-inflammatory effects of hydrogen sulfide (H₂S) on DACD. Methods: We used a behavioural scoring method, Western blot, TUNEL staining and immunofluorescence staining to investigate the expression of the mitochondrial apoptotic pathway and the IL-23/IL-17 axis in db/db mice with or without sodium hydrosulfide (NaHS) administration. Results: NaHS administration mice exhibited reduced time to find the platform and a shorter swimming distance (P<0.05), while the time spent in the target quadrant was increased compared to that of the db/db group (P<0.05). Pro-apoptotic proteins, including cleaved Caspase-3, cleaved Caspase-9, Bax and cytochrome C, were elevated in the db/db group (P<0.01) but were downregulated in the db/db+NaHS group (P<0.05). Exogenous H₂S decreased the numbers of TUNEL-positive cells in the db/db mice (P<0.05). The Western blot analysis showed that the expression levels of IL-23/IL-17 were lower in the NaHS administration group than in the db/db group (P<0.05). Conclusion: We demonstrated that H₂S improved the spatial learning and memory abilities of the db/db mice by modulating the mitochondrial apoptotic pathway and the IL-23/IL-17 axis, which were found to be associated with DACD. H₂S treatment may help prevent the progression of apoptotic hippocampal neurons in db/db mice and inform the development of a new therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Exogenous Hydrogen Sulfide Ameliorates Diabetes-Associated Cognitive Decline by Regulating the Mitochondria-Mediated Apoptotic Pathway and IL-23/IL-17 Expression in db/db Mice

Zhong

et al. 2017

Cell Physiol Biochem

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“…At later stages, changes in the expression or assembly of some components of the respiratory chain may occur and these are typically associated with impaired functionality [98,99]. The glucose-induced changes in the mitochondrial superoxide production are reversible: normalization of the membrane potential suppresses the ROS production in endothelial cells [26,35,83,94,100]. While elevated mitochondrial membrane potential is detectable in endothelial cells exposed to high glucose concentration, the overexpression of either uncoupling protein 1 (UCP1) or uncoupling protein 2 (UCP2) normalizes the membrane potential and reduces the ROS production [26,35,83].…”

Section: The Mechanism Of Glucose-induced Mitochondrial Superoxide Gementioning

confidence: 99%

“…The function of UCP2 is regulated by ROS itself: the proton conductance of the protein is controlled by glutathionylation, and if ROS is present, it increases the proton leakage, whereas in the absence of ROS, the channel closes, thus this feedback may control the mitochondrial potential and the ROS production simultaneously [32,33]. Furthermore, hydrogen sulfide donors that normalize the mitochondrial potential by electron supplementation via sulfide:quinone oxidoreductase (SQR) also inhibit the superoxide generation induced by hyperglycemia [94,100].…”

Section: The Mechanism Of Glucose-induced Mitochondrial Superoxide Gementioning

confidence: 99%

Hyperglycemia-Induced Endothelial Dysfunction

Gerö¹

2018

Endothelial Dysfunction - Old Concepts and New Challenges

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Glucose-induced endothelial dysfunction plays a fundamental role in the development of diabetic vascular complications and glycemic control (the foundation of diabetes care) provides limited protection against the cardiovascular complications. Therefore, identification of novel drug targets and treatment approaches for diabetes complications represent a key direction of current pharmaceutical research. The "unifying theory" of hyperglycemia-induced endothelial cell injury organizes the events of cellular dysfunction in a linear cascade and identifies mitochondrial superoxide generation as the triggering event of the injury. Exposure to high glucose concentration for long periods or repeated glycemic swings may induce changes in metabolic substrate availability and lead to mitochondrial hyperpolarization. Changes in the mitochondrial membrane potential induce superoxide production by the electron transport chain and result in oxidative stress. Mitochondrial superoxide is also responsible for the induction of other sources of reactive oxygen species (ROS) within the cells, including advanced glycation end products (AGEs) and the NADPH oxidase. Mitochondria also show morphological changes and impaired assembly of the respiratory complexes occurs, which results in cellular energy failure, cell senescence and vascular dysfunction. Current intervention strategies aim to inhibit the mitochondrial ROS production and novel therapeutic approaches are expected to provide valuable tools in diabetes therapy in the upcoming years.

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“…Hyperglycemia is characteristic of type 2 diabetes and the metabolic syndrome, where high levels of glucose in the blood lead to intracellular oxidative stress, especially in tissues involved in glucose metabolism [1][2][3]. Although mitochondria are a source of oxidative stress, they are also a principal target of attack by reactive oxygen and nitrogen species [4,5] and, once above certain thresholds, insulin sensitivity and secretion are hampered [6,7].…”

Section: Introductionmentioning

confidence: 99%

Quercetin preserves redox status and stimulates mitochondrial function in metabolically-stressed HepG2 cells

Houghton

Kerimi

Tumova

et al. 2018

Free Radical Biology and Medicine

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ReuseThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can't change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. AbstractHyperglycemia augments formation of intracellular reactive oxygen species (ROS) with associated mitochondrial damage and increased risk of insulin resistance in type 2 diabetes. We examined whether quercetin could reverse chronic high glucose-induced oxidative stress and mitochondrial dysfunction. Following long-term high glucose treatment, complex I activity was significantly decreased in isolated mitochondria from HepG2 cells. Quercetin dose-dependently recovered complex I activity and lowered cellular ROS generation under both high and normal glucose conditions. Respirometry studies showed that quercetin could counteract the detrimental increase in inner mitochondrial membrane proton leakage resulting from high glucose while it increased oxidative respiration, despite a decrease in electron transfer system (ETS) capacity, and lower non-ETS oxygen consumption. A quercetin-stimulated increase in cellular NAD + /NADH was evident within 2 h and a two-fold increase in PGC-1 mRNA within 6 h, in both normal and high glucose conditions. A similar pattern was also found for the mRNA expression of the repulsive guidance molecule b (RGMB) and its long non-coding RNA (lncRNA) RGMB-AS1 with quercetin, indicating a potential change of the glycolytic phenotype and suppression of aberrant cellular growth which is characteristic of the HepG2 cells. Direct effects of quercetin on PGC-1 activity were minimal, as quercetin only weakly enhanced PGC-1 binding to PPAR in vitro at higher concentrations. Our results suggest that quercetin may protect mitochondrial function from high glucose-induced stress by increasing cellular NAD + /NADH and activation of PGC-1 -mediated pathways. Lower ROS in combination with improved complex I activity and ETS coupling efficiency under conditions of amplified oxidative stress could reinforce mitochondrial integrity and improve redox status, beneficial in certain metabolic diseases. Abbreviations oxygen species; ROXresidual oxygen consumption; SIRTsirtuin; TBP -TATA-box binding protein; TFAMmitochondrial transcription factor A; TR-FRETtime-resolved fluorescence energy transfer.Graphical Abstract:

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The novel mitochondria-targeted hydrogen sulfide (H 2 S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro

Abstract: Graphical abstract

Cited by 140 publications

References 65 publications

Exogenous Hydrogen Sulfide Ameliorates Diabetes-Associated Cognitive Decline by Regulating the Mitochondria-Mediated Apoptotic Pathway and IL-23/IL-17 Expression in db/db Mice

Exogenous Hydrogen Sulfide Ameliorates Diabetes-Associated Cognitive Decline by Regulating the Mitochondria-Mediated Apoptotic Pathway and IL-23/IL-17 Expression in db/db Mice

Hyperglycemia-Induced Endothelial Dysfunction

Quercetin preserves redox status and stimulates mitochondrial function in metabolically-stressed HepG2 cells

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