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Controllable hydrogen sulfide donors and their activity against myocardial ischemia-reperfusion injury.

ABSTRACT: Hydrogen sulfide (H2S), known as an important cellular signaling molecule, plays critical roles in many physiological and/or pathological processes. Modulation of H2S levels could have tremendous therapeutic value. However, the study on H2S has been hindered due to the lack of controllable H2S releasing agents that could mimic the slow and moderate H2S release in vivo. In this work we report the design, synthesis, and biological evaluation of a new class of controllable H2S donors. Twenty-five donors were prepared and tested. Their structures were based on a perthiol template, which was suggested to be involved in H2S biosynthesis. H2S release mechanism from these donors was studied and proved to be thiol-dependent. We also developed a series of cell-based assays to access their H2S-related activities. H9c2 cardiac myocytes were used in these experiments. We tested lead donors' cytotoxicity and confirmed their H2S production in cells. Finally we demonstrated that selected donors showed potent protective effects in an in vivo murine model of myocardial ischemia-reperfusion injury, through a H2S-related mechanism.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC3744587 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Controllable hydrogen sulfide donors and their activity against myocardial ischemia-reperfusion injury.

Zhao Yu Y Bhushan Shashi S Yang Chuntao C Otsuka Hiroyuki H Stein Jason D JD Pacheco Armando A Peng Bo B Devarie-Baez Nelmi O NO Aguilar Hector C HC Lefer David J DJ Xian Ming M

ACS chemical biology 20130416 6

Hydrogen sulfide (H2S), known as an important cellular signaling molecule, plays critical roles in many physiological and/or pathological processes. Modulation of H2S levels could have tremendous therapeutic value. However, the study on H2S has been hindered due to the lack of controllable H2S releasing agents that could mimic the slow and moderate H2S release in vivo. In this work we report the design, synthesis, and biological evaluation of a new class of controllable H2S donors. Twenty-five d ...[more]

PMID: 23547844

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Project description:The aim of the present study was to explore the effect of exogenous hydrogen sulphide (H2S) on endoplasmic reticulum (ER) stress (ERS) in a rat model of hepatic ischemia/reperfusion (I/R) injury. A total of 48 Sprague-Dawley rats were randomly divided into four groups (n=12/group) as follows: Sham, I/R, I/R preceded by NaHS (I/R-NaHS) and I/R preceded by L-C-propargylglycine (PAG), a H2S inhibitor (I/R-PAG). With the exception of the sham group, the rats in the other groups were subjected to 30 min hepatic warm ischemia followed by reperfusion for 6 or 12 h. Hepatic function was evaluated by serum concentrations of alanine aminotransferase (ALT). Apoptosis of hepatic cells was assessed by TUNEL staining and measurement of caspase-12 expression. The expression levels of ERS-associated proteins and mRNAs of pancreatic ER eukaryotic translation initiation factor-2a kinase (PERK), activating transcription factor-6 (ATF6), glucose-regulated protein (GRP) 78, TNF-receptor-associated factor (TRAF)-2, C/EBP homologous protein (CHOP) and caspase-12 were also measured by western blotting and reverse transcription-quantitative PCR. The serum concentrations of ALT in the I/R and I/R-PAG groups were found to be significantly higher compared with those in the sham and I/R-NaHS groups after 6 h of reperfusion; in addition, the ALT level returned to normal in the I/R group, while it increased further in the I/R-PAG group after 12 h of reperfusion. A higher cell apoptosis rate was observed in the I/R and I/R-PAG groups and the highest cell apoptosis rate was observed in the I/R-PAG group; correspondingly, the expression of caspase-12 was increased in the I/R and I/R-PAG groups. H2S appeared to significantly attenuate hepatic I/R-induced ERS response, as indicated by the decreased expression of ATF6, PERK, GRP78, TRAF2 and CHOP. Endogenous H2S may serve a hepatoprotective function after I/R, and inhibition of endogenous H2S results in aggravation of I/R damage. Exogenous H2S was shown to inhibit ERS-related gene expression, leading to suppression of inflammatory reaction and improvement of I/R damage. Therefore, exogenous H2S has therapeutic potential to alleviate hepatic I/R injury.

Dataset Information

Controllable hydrogen sulfide donors and their activity against myocardial ischemia-reperfusion injury.

Publications

Controllable hydrogen sulfide donors and their activity against myocardial ischemia-reperfusion injury.

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