Hydrogen sulfide preconditions the<i>db/db</i>diabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner

Peake, Bridgette F.; Nicholson, Chad K.; Lambert, Jonathan P; Hood, Rebecca L.; Amin, Hena; Amin, Sana; Calvert, John W.

doi:10.1152/ajpheart.00796.2012

Cited by 149 publications

(129 citation statements)

References 38 publications

(47 reference statements)

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“…Exogenous H 2 S therapy has been demonstrated to attenuate myocardial I/R injury in mice (7,8,12). To determine whether the protective mechanism is dependent on eNOS, we first used a mouse model with global genetic ablation of eNOS.…”

Section: H 2 S Therapy Restores Enos Function and No Bioavailability mentioning

confidence: 99%

Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent

King

Polhemus

Bhushan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Previous studies have demonstrated that hydrogen sulfide (H 2 S) protects against multiple cardiovascular disease states in a similar manner as nitric oxide (NO). H 2 S therapy also has been shown to augment NO bioavailability and signaling. The purpose of this study was to investigate the impact of H 2 S deficiency on endothelial NO synthase (eNOS) function, NO production, and ischemia/reperfusion (I/R) injury. We found that mice lacking the H 2 S-producing enzyme cystathionine γ-lyase (CSE) exhibit elevated oxidative stress, dysfunctional eNOS, diminished NO levels, and exacerbated myocardial and hepatic I/R injury. In CSE KO mice, acute H 2 S therapy restored eNOS function and NO bioavailability and attenuated I/R injury. In addition, we found that H 2 S therapy fails to protect against I/R in eNOS phosphomutant mice (S1179A). Our results suggest that H 2 S-mediated cytoprotective signaling in the setting of I/R injury is dependent in large part on eNOS activation and NO generation.eNOS uncoupling | myocardial infarction | cystathionase | Cth | nitrite H ydrogen sulfide (H 2 S), historically known for its odorous smell and toxicity at high concentrations, has recently been classified as a physiological signaling molecule with robust cytoprotective actions in multiple organ systems (1-3). H 2 S is produced enzymatically in mammalian tissues by three different enzymes: cystathionine γ-lyase (CSE), cystathionine beta-synthase (CBS), and 3-mercatopyruvate sulfurtransferase (3-MST). CSE, involved in the cysteine biosynthesis pathway, coordinates with L-cystine to produce H 2 S within the vasculature and is known to regulate blood pressure, modulate cellular metabolism, promote angiogenesis, regulate ion channels, and mitigate fibrosis and inflammation (4). Endothelial nitric oxide synthase (eNOS) catalyzes the production of nitric oxide (NO) from L-arginine within the endothelium to regulate vascular tone via cGMP signaling in vascular smooth muscle, mitochondrial respiration, platelet function, inflammation, and angiogenesis. The biological profiles of H 2 S and NO are similar, and both molecules are known to protect cells against various injurious states that result in organ injury. Although H 2 S and NO are thought to modulate independent signaling pathways, there is limited evidence of cross-talk between these two molecules (5, 6).H 2 S therapeutics and endogenous overexpression of CSE have been shown to attenuate ischemia/reperfusion (I/R) injury (7,8). Similarly, NO therapy and eNOS gene overexpression are also protective in ischemic disease states (9). Given the potent antioxidant actions of H 2 S (10, 11) and the effects of exogenous H 2 S therapy on NO bioavailability (5, 8), we investigated the effects of genetic deletion of the cystathionase gene (Cth, i.e., CSE KO) on the regulation of eNOS function and NO bioavailability. ResultsSulfide Levels are Reduced in CSE KO Mice. Whole blood and heart specimens were collected from WT and CSE KO mice to measure H 2 S levels using a high-sensitivity gas chromato...

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Section: H 2 S Therapy Restores Enos Function and No Bioavailability mentioning

confidence: 99%

Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent

King

Polhemus

Bhushan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

315

306

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“…However, there are no published data on the potential effect of H 2 S on accelerated atherosclerosis in diabetes. Some recent studies indicate that H 2 S is cytoprotective during myocardial ischemia-reperfusion injury in the setting of diabetes by alleviating oxidative stress, and the ability of H 2 S to upregulate cellular antioxidants in the heart in a Nrf2-dependent manner (12)(13)(14). H 2 S may therefore play an important role in diabetes-accelerated atherosclerosis, and the effects of H 2 S may be mediated via activation of Nrf2.…”

Section: Diabetes Leads To a Marked Increase In Atherosclerosis (1)mentioning

confidence: 99%

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

et al. 2016

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Hydrogen sulfide (H2S) has been shown to have powerful antioxidative and anti-inflammatory properties that can regulate multiple cardiovascular functions. However, its precise role in diabetes-accelerated atherosclerosis remains unclear. We report here that H2S reduced aortic atherosclerotic plaque formation with reduction in superoxide (O2−) generation and the adhesion molecules in streptozotocin (STZ)-induced LDLr−/− mice but not in LDLr−/−Nrf2−/− mice. In vitro, H2S inhibited foam cell formation, decreased O2− generation, and increased nuclear factor erythroid 2–related factor 2 (Nrf2) nuclear translocation and consequently heme oxygenase 1 (HO-1) expression upregulation in high glucose (HG) plus oxidized LDL (ox-LDL)–treated primary peritoneal macrophages from wild-type but not Nrf2−/− mice. H2S also decreased O2− and adhesion molecule levels and increased Nrf2 nuclear translocation and HO-1 expression, which were suppressed by Nrf2 knockdown in HG/ox-LDL–treated endothelial cells. H2S increased S-sulfhydration of Keap1, induced Nrf2 dissociation from Keap1, enhanced Nrf2 nuclear translocation, and inhibited O2− generation, which were abrogated after Keap1 mutated at Cys151, but not Cys273, in endothelial cells. Collectively, H2S attenuates diabetes-accelerated atherosclerosis, which may be related to inhibition of oxidative stress via Keap1 sulfhydrylation at Cys151 to activate Nrf2 signaling. This may provide a novel therapeutic target to prevent atherosclerosis in the context of diabetes.

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“…oxidative stress, leading to myocardial damage (5,8,9). For this reason, curcumin, which has antioxidant effects, has been used to prevent diabetic cardiomyopathy in rats with streptozotocin (STZ)-induced diabetes (10).…”

Section: Exogenous Hydrogen Sulfide Protects H9c2 Cardiac Cells Againmentioning

confidence: 99%

“…In our previous studies, we demonstrated that exogenous H 2 S protects H9c2 cardiac cells against chemical hyoxia-induced injury by inhibiting oxidative stress and upregulating heat shock protein 90 (HSP90) expression (19,20). To date, the role of H 2 S in diabetes-induced cardiac damage has attracted considerable attention due to to its antioxidant (9,(19)(20)(21) and modulatory effects on the signaling pathways, including MAPK pathways (22,23). Recently, H 2 S has been shown to provide protection against cardiomyopathy and vascular dysfunction in models of STZ-induced diabetes (24).…”

Section: Exogenous Hydrogen Sulfide Protects H9c2 Cardiac Cells Againmentioning

confidence: 99%

Exogenous hydrogen sulfide protects H9c2 cardiac cells against high glucose-induced injury by inhibiting the activities of the p38 MAPK and ERK1/2 pathways

Wang

Chen

et al. 2013

International Journal of Molecular Medicine

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Abstract. Hyperglycemia is a risk factor for the development of diabetic cardiovascular complications, which are associated with the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, we demonstrate the inhibitory effects of exogenous hydrogen sulfide (H 2 S) on the activation of the MAPK pathway. The aim of the present study was to determine whether exogenous H 2 S prevents high glucose (HG)-induced injury by inhibiting the activation of the p38 MAPK and extracellular signal-regulated kinase (ERK)1/2 (members of MAPK) pathways in cardiomyoblasts (H9c2 cells). The findings of the present study demonstrated that the treatment of H9c2 cells with HG (35 mM glucose) for 24 h not only significantly induced injury, including cytotoxicity, apoptosis, overproduction of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (MMP), but also upregulated the expression levels of phosphorylated (p)-p38 MAPK and p-ERK1/2. The increased expression levels of p-p38 MAPK and p-ERK1/2 were markedly reduced by pre-treatment of the H9c2 cells with 400 µM sodium hydrogen sulfide (NaHS; a donor of H 2 S) prior to exposure to 35 mM glucose. Importantly, pre-treatment of the cells with 400 µM NaHS or 3 µM SB203580 (a selective inhibitor of p38 MAPK) or 15 µM U0126 (a selective inhibitor of ERK1/2) attenuated the HG-induced cardiomyocyte injury, leading to an increase in cell viability and a decrease in the number of apoptotic cells, preventing ROS generation, as well as the loss of MMP. In addition, pre-treatment of the cells with 1,000 µM N-acetyl-L-cysteine (a ROS scavenger) prior to exposure to HG ameliorated the HG-induced cytotoxicity. Taken together, the data from the present study demonstrate for the first time, to our knowledge, that exogenous H 2 S exerts a protective effect against HG-induced injury by inhibiting the activation of the p38 MAPK and ERK1/2 pathways and preventing oxidative stress in H9c2 cells.

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

Cited by 149 publications

References 38 publications

Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent

Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

Exogenous hydrogen sulfide protects H9c2 cardiac cells against high glucose-induced injury by inhibiting the activities of the p38 MAPK and ERK1/2 pathways

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