TY - JOUR
T1 - Hydrogen sulfide increases nitric oxide production with calcium-dependent activation of endothelial nitric oxide synthase in endothelial cells
AU - Kida, Michiya
AU - Sugiyama, Toru
AU - Yoshimoto, Takanobu
AU - Ogawa, Yoshihiro
N1 - Funding Information:
This study was supported in part by the Grant-in-aid from the Ministry of Education, Science, Sports and Culture, and the Ministry of Health, Welfare and Labor of Japan. This study was also supported by a grant from the Takeda Science Foundation (to T.S.).
Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/1/23
Y1 - 2013/1/23
N2 - Hydrogen sulfide (H2S) was recently discovered to be synthesized in mammalian tissues by several different enzymes. Numerous studies have shown that H2S has vasodilator and antihypertensive effects in the cardiovascular system. However, intracellular mechanisms of the H 2S-induced vasodilation and its interactions with other endothelium-derived relaxing factors, such as nitric oxide (NO), remain unclear. We investigated whether H2S directly regulates endothelial NO synthase (eNOS) activity and NO production in endothelial cells. NaHS, a H 2S donor, dose-dependently increased NO production in cultured endothelial cells. This effect was abolished by a calcium chelator (BAPTA-AM), but not by the absence of extracellular calcium. The NaHS-induced NO production was partially blocked by inhibitors of ryanodine receptor (dantrolene) or inositol 1,4,5-triphosphate receptor (xestospongin C). NaHS significantly increased intracellular calcium concentrations, and this effect was attenuated by dantrolene or xestospongin C. NaHS induced phosphorylation of eNOS at the activating phosphoserine residue 1179. The NaHS-induced eNOS phosphorylation and NO production were not affected by a PI3K/Akt inhibitor (wortmannin). The data of this study suggest that H2S directly acts on endothelial cells to induce eNOS activation and NO production by releasing calcium from the intracellular store in endoplasmic reticulum, which may explain one of mechanisms of its vasodilator function.
AB - Hydrogen sulfide (H2S) was recently discovered to be synthesized in mammalian tissues by several different enzymes. Numerous studies have shown that H2S has vasodilator and antihypertensive effects in the cardiovascular system. However, intracellular mechanisms of the H 2S-induced vasodilation and its interactions with other endothelium-derived relaxing factors, such as nitric oxide (NO), remain unclear. We investigated whether H2S directly regulates endothelial NO synthase (eNOS) activity and NO production in endothelial cells. NaHS, a H 2S donor, dose-dependently increased NO production in cultured endothelial cells. This effect was abolished by a calcium chelator (BAPTA-AM), but not by the absence of extracellular calcium. The NaHS-induced NO production was partially blocked by inhibitors of ryanodine receptor (dantrolene) or inositol 1,4,5-triphosphate receptor (xestospongin C). NaHS significantly increased intracellular calcium concentrations, and this effect was attenuated by dantrolene or xestospongin C. NaHS induced phosphorylation of eNOS at the activating phosphoserine residue 1179. The NaHS-induced eNOS phosphorylation and NO production were not affected by a PI3K/Akt inhibitor (wortmannin). The data of this study suggest that H2S directly acts on endothelial cells to induce eNOS activation and NO production by releasing calcium from the intracellular store in endoplasmic reticulum, which may explain one of mechanisms of its vasodilator function.
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U2 - 10.1016/j.ejps.2012.11.001
DO - 10.1016/j.ejps.2012.11.001
M3 - Article
C2 - 23148920
AN - SCOPUS:84870383811
VL - 48
SP - 211
EP - 215
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
SN - 0928-0987
IS - 1-2
ER -