National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan; Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan; SOKENDAI, Department of Physiological Sciences, Okazaki, 444-8787, Japan
Tomohiro Tanaka
National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan; Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan; Center for Novel Science Initiatives (CNSI), National Institutes of Natural Sciences, Tokyo, 105-0001, Japan
Kakeru Shimoda
National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan; Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan; SOKENDAI, Department of Physiological Sciences, Okazaki, 444-8787, Japan; Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
Tomoaki Ida
Organization for Research Promotion, Osaka Metropolitan University, Sakai, 599-8531, Japan; Graduate School of Medicine, Tohoku University, Sendai, 980-8575, Japan
Shota Sasaki
Graduate School of Engineering, Tohoku University, Sendai, 980-8579, Japan
Keitaro Umezawa
Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, 173-0015, Japan
Hiromi Imamura
Organization of Research Initiatives, Yamaguchi University, Yamaguchi, 753-8515, Japan
Yasuteru Urano
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
Fumito Ichinose
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
Toshiro Kaneko
Graduate School of Engineering, Tohoku University, Sendai, 980-8579, Japan
Takaaki Akaike
Graduate School of Medicine, Tohoku University, Sendai, 980-8575, Japan
Motohiro Nishida
National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan; Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan; SOKENDAI, Department of Physiological Sciences, Okazaki, 444-8787, Japan; Center for Novel Science Initiatives (CNSI), National Institutes of Natural Sciences, Tokyo, 105-0001, Japan; Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan; Corresponding author. Department of Physiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Ischemic heart disease is the main global cause of death in the world. Abnormal sulfide catabolism, especially hydrogen sulfide accumulation, impedes mitochondrial respiration and worsens the prognosis after ischemic insults, but the substantial therapeutic strategy has not been established. Non-thermal atmospheric pressure plasma irradiation therapy is attracted attention as it exerts beneficial effects by producing various reactive molecular species. Growing evidence has suggested that supersulfides, formed by catenation of sulfur atoms, contribute to various biological processes involving electron transfer in cells. Here, we report that non-thermal plasma-irradiated cysteine (Cys∗) protects mouse hearts against ischemia/reperfusion (I/R) injury by preventing supersulfide catabolism. Cys∗ has a weak but long-lasting supersulfide activity, and the treatment of rat cardiomyocytes with Cys∗ prevents mitochondrial dysfunction after hypoxic stress. Cys∗ increases sulfide-quinone oxidoreductase (SQOR), and silencing SQOR abolishes Cys∗-induced supersulfide formation and cytoprotection. Local administration of mouse hearts with Cys∗ significantly reduces infarct size with preserving supersulfide levels after I/R. These results suggest that maintaining supersulfide formation through SQOR underlies cardioprotection by Cys∗ against I/R injury.
