The Gasotransmitter Hydrogen Sulfide Induces Nrf2-Target Genes by Inactivating the Keap1 Ubiquitin Ligase Substrate Adaptor Through Formation of a Disulfide Bond Between Cys-226 and Cys-613

Hourihan, John M.; Kenna, J. Gerry; Hayes, John D.

doi:10.1089/ars.2012.4944

Cited by 189 publications

(179 citation statements)

References 73 publications

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“…This suggests that there are cysteine residues other than the three residues discussed here that are critical for Keap1 sensor activity. Indeed, Cys226, Cys434, and Cys613 have been suggested to be important for Nrf2 activation (35,36), although further biological investigations utilizing an evaluation system similar to the one used here are necessary to confirm this. An important but remaining issue is how these Keap1 cysteine modifications provoked by the Nrf2-inducing chemicals actually cause the stabilization and accumulation of Nrf2.…”

Section: Discussionmentioning

confidence: 76%

Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response

Saito

Suzuki

Hiramoto

et al. 2016

Molecular and Cellular Biology

212

222

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The Keap1-Nrf2 system plays a central role in cytoprotection against electrophilic/oxidative stresses. Although Cys151, Cys273, and Cys288 of Keap1 are major sensor cysteine residues for detecting these stresses, it has not been technically feasible to evaluate the functionality of Cys273 or Cys288, since Keap1 mutants that harbor substitutions in these residues and maintain the ability to repress Nrf2 accumulation do not exist. To overcome this problem, we systematically introduced amino acid substitutions into Cys273/Cys288 and finally identified Cys273Trp and Cys288Glu mutations that do not affect Keap1's ability to repress Nrf2 accumulation. Utilizing these Keap1 mutants, we generated stable murine embryonic fibroblast (MEF) cell lines and knock-in mouse lines. Our analyses with the MEFs and peritoneal macrophages from the knock-in mice revealed that three major cysteine residues, Cys151, Cys273, and Cys288, individually and/or redundantly act as sensors. Based on the functional necessity of these three cysteine residues, we categorized chemical inducers of Nrf2 into four classes. Class I and II utilizes Cys151 and Cys288, respectively, while class III requires all three residues (Cys151/Cys273/Cys288), while class IV inducers function independently of all three of these cysteine residues. This study thus demonstrates that Keap1 utilizes multiple cysteine residues specifically and/or collaboratively as sensors for the detection of a wide range of environmental stresses.

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Section: Discussionmentioning

confidence: 76%

Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response

Saito

Suzuki

Hiramoto

et al. 2016

Molecular and Cellular Biology

212

222

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“…However, the anti-oxidant activity of H 2 S is due to further and more complex mechanisms, such as the activation of powerful endogenous mechanisms, such as the Nrf2-mediated "anti-oxidant" machinery [36], possibly involved also in the cardioprotective effects of H 2 S [13]. Indeed, in experimental models of cardiac I/R, H 2 S-donors such as GYY4137 were found to strongly inhibit oxidative stress in myocardial tissue [30].…”

Section: Discussionmentioning

confidence: 99%

The novel H 2 S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoK ATP channels and reduction of oxidative stress

Testai

Marino

Piano

et al. 2016

Pharmacological Research

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a b s t r a c tThe endogenous gasotransmitter hydrogen sulphide (H 2 S) is an important regulator of the cardiovascular system, particularly of myocardial function. Moreover, H 2 S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury, and is considered an important mediator of "ischemic preconditioning", through activation of mitochondrial potassium channels, reduction of oxidative stress, activation of the endogenous "anti-oxidant machinery" and limitation of inflammatory responses. Accordingly, H 2 S-donors, i.e. pro-drugs able to generate exogenous H 2 S, are viewed as promising therapeutic agents for a number of cardiovascular diseases. The novel H 2 S-donor 4-carboxy phenylisothiocyanate (4CPI), whose vasorelaxing effects were recently reported, was tested here in different experimental models of myocardial I/R.In Langendorff-perfused rat hearts subjected to I/R, 4CPI significantly improved the post-ischemic recovery of myocardial functional parameters and limited tissue injury. These effects were antagonized by 5-hydroxydecanoic acid (a blocker of mitoK ATP channels). Moreover, 4CPI inhibited the formation of reactive oxygen species. We found the whole battery of H 2 S-producing enzymes to be present in myocardial tissue: cystathionine ␥-lyase (CSE), cystathionine ␤-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST). Notably, 4CPI down-regulated the post-ischemic expression of CSE.In Langendorff-perfused mouse hearts, 4CPI reduced the post-ischemic release of norepinephrine and the incidence of ventricular arrhythmias. In both rat and mouse hearts, 4CPI did not affect the degranulation of resident mast cells.In isolated rat cardiac mitochondria, 4CPI partially depolarized the mitochondrial membrane potential; this effect was antagonized by ATP (i.e., the physiological inhibitor of K ATP channels). Moreover, 4CPI abrogated calcium uptake in the mitochondrial matrix.Finally, in an in vivo model of acute myocardial infarction in rats, 4CPI significantly decreased I/Rinduced tissue injury.In conclusion, H 2 S-donors, and in particular isothiocyanate-based H2S-releasing drugs like 4CPI, can actually be considered a suitable pharmacological option in anti-ischemic therapy.

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“…Upon stimulation, Nrf2 dissociates from Keap1 and translocates to the nucleus (16). H 2 S has recently been shown to sulfhydrate Keap1, which results in the release and translocation of Nrf2 to the nucleus (10,34). Recent findings also indicate that Keap1 acts as a shuttle protein, suggesting that it has a functional role not only in the cytoplasm but also in the nucleus (18,26).…”

Section: Discussionmentioning

confidence: 99%

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

149

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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The Gasotransmitter Hydrogen Sulfide Induces Nrf2-Target Genes by Inactivating the Keap1 Ubiquitin Ligase Substrate Adaptor Through Formation of a Disulfide Bond Between Cys-226 and Cys-613

Abstract: Inhibition of Keap1 by H2S leads to Nrf2-mediated induction of cytoprotective genes. Nrf2 controls Cbs, Cse, and Sqrdl, suggesting that a feedback loop exists between Nrf2 and H2S.

Cited by 189 publications

References 73 publications

Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response

Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response

The novel H 2 S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoK ATP channels and reduction of oxidative stress

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

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