Thiosulfate mediates cytoprotective effects of hydrogen sulfide against neuronal ischemia

Eizo Marutani, Marina Yamada, Tomoaki Ida, Kentaro Tokuda, Kohei Ikeda, Shinichi Kai, Kazuhiro Shirozu, Kei Hayashida, Shizuko Kosugi, Kenjiro Hanaoka, Masao Kaneki, Takaaki Akaike, Fumito Ichinose

研究成果: ジャーナルへの寄稿記事

27 引用 (Scopus)

抄録

Background-Hydrogen sulfide (H2S) exhibits protective effects in various disease models including cerebral ischemia-reperfusion (I/R) injury. Nonetheless, mechanisms and identity of molecules responsible for neuroprotective effects of H2S remain incompletely defined. In the current study, we observed that thiosulfate, an oxidation product of H2S, mediates protective effects of an H2S donor compound sodium sulfide (Na2S) against neuronal I/R injury. Methods and Results-We observed that thiosulfate in cell culture medium is not only required but also sufficient to mediate cytoprotective effects of Na2S against oxygen glucose deprivation and reoxygenation of human neuroblastoma cell line (SH-SY5Y) and murine primary cortical neurons. Systemic administration of sodium thiosulfate (STS) improved survival and neurological function of mice subjected to global cerebral I/R injury. Beneficial effects of STS, as well as Na2S, were associated with marked increase of thiosulfate, but not H2S, in plasma and brain tissues. These results suggest that thiosulfate is a circulating "carrier" molecule of beneficial effects of H2S. Protective effects of thiosulfate were associated with inhibition of caspase-3 activity by persulfidation at Cys163 in caspase-3. We discovered that an SLC13 family protein, sodium sulfate cotransporter 2 (SLC13A4, NaS-2), facilitates transport of thiosulfate, but not sulfide, across the cell membrane, regulating intracellular concentrations and thus mediating cytoprotective effects of Na2S and STS. Conclusions-The protective effects of H2S are mediated by thiosulfate that is transported across cell membrane by NaS-2 and exerts antiapoptotic effects via persulfidation of caspase-3. Given the established safety track record, thiosulfate may be therapeutic against ischemic brain injury.

元の言語英語
記事番号e002125
ジャーナルJournal of the American Heart Association
4
発行部数11
DOI
出版物ステータス出版済み - 11 1 2015

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Thiosulfates
Hydrogen Sulfide
Ischemia
Reperfusion Injury
Caspase 3
Brain Ischemia
Cell Membrane
Neuroprotective Agents
Sulfides
Neuroblastoma
Brain Injuries
Culture Media
Cell Culture Techniques
sodium sulfide
Oxygen
Safety
Neurons
Glucose
Cell Line
Survival

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

これを引用

Thiosulfate mediates cytoprotective effects of hydrogen sulfide against neuronal ischemia. / Marutani, Eizo; Yamada, Marina; Ida, Tomoaki; Tokuda, Kentaro; Ikeda, Kohei; Kai, Shinichi; Shirozu, Kazuhiro; Hayashida, Kei; Kosugi, Shizuko; Hanaoka, Kenjiro; Kaneki, Masao; Akaike, Takaaki; Ichinose, Fumito.

:: Journal of the American Heart Association, 巻 4, 番号 11, e002125, 01.11.2015.

研究成果: ジャーナルへの寄稿記事

Marutani, E, Yamada, M, Ida, T, Tokuda, K, Ikeda, K, Kai, S, Shirozu, K, Hayashida, K, Kosugi, S, Hanaoka, K, Kaneki, M, Akaike, T & Ichinose, F 2015, 'Thiosulfate mediates cytoprotective effects of hydrogen sulfide against neuronal ischemia', Journal of the American Heart Association, 巻. 4, 番号 11, e002125. https://doi.org/10.1161/JAHA.115.002125
Marutani, Eizo ; Yamada, Marina ; Ida, Tomoaki ; Tokuda, Kentaro ; Ikeda, Kohei ; Kai, Shinichi ; Shirozu, Kazuhiro ; Hayashida, Kei ; Kosugi, Shizuko ; Hanaoka, Kenjiro ; Kaneki, Masao ; Akaike, Takaaki ; Ichinose, Fumito. / Thiosulfate mediates cytoprotective effects of hydrogen sulfide against neuronal ischemia. :: Journal of the American Heart Association. 2015 ; 巻 4, 番号 11.
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abstract = "Background-Hydrogen sulfide (H2S) exhibits protective effects in various disease models including cerebral ischemia-reperfusion (I/R) injury. Nonetheless, mechanisms and identity of molecules responsible for neuroprotective effects of H2S remain incompletely defined. In the current study, we observed that thiosulfate, an oxidation product of H2S, mediates protective effects of an H2S donor compound sodium sulfide (Na2S) against neuronal I/R injury. Methods and Results-We observed that thiosulfate in cell culture medium is not only required but also sufficient to mediate cytoprotective effects of Na2S against oxygen glucose deprivation and reoxygenation of human neuroblastoma cell line (SH-SY5Y) and murine primary cortical neurons. Systemic administration of sodium thiosulfate (STS) improved survival and neurological function of mice subjected to global cerebral I/R injury. Beneficial effects of STS, as well as Na2S, were associated with marked increase of thiosulfate, but not H2S, in plasma and brain tissues. These results suggest that thiosulfate is a circulating {"}carrier{"} molecule of beneficial effects of H2S. Protective effects of thiosulfate were associated with inhibition of caspase-3 activity by persulfidation at Cys163 in caspase-3. We discovered that an SLC13 family protein, sodium sulfate cotransporter 2 (SLC13A4, NaS-2), facilitates transport of thiosulfate, but not sulfide, across the cell membrane, regulating intracellular concentrations and thus mediating cytoprotective effects of Na2S and STS. Conclusions-The protective effects of H2S are mediated by thiosulfate that is transported across cell membrane by NaS-2 and exerts antiapoptotic effects via persulfidation of caspase-3. Given the established safety track record, thiosulfate may be therapeutic against ischemic brain injury.",
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AU - Marutani, Eizo

AU - Yamada, Marina

AU - Ida, Tomoaki

AU - Tokuda, Kentaro

AU - Ikeda, Kohei

AU - Kai, Shinichi

AU - Shirozu, Kazuhiro

AU - Hayashida, Kei

AU - Kosugi, Shizuko

AU - Hanaoka, Kenjiro

AU - Kaneki, Masao

AU - Akaike, Takaaki

AU - Ichinose, Fumito

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