The mechanisms responsible for the cardioprotective effect of hydrogen sulfide (H2S) are unclear. The present study was designed to examine whether H2S could regulate hyperhomocysteinemia (HHcy)-induced cardiomyocytic endoplasmic reticulum (ER) stress. A rat model of HHcy was produced, and H9c2 cells (rat embryonic heart–derived cell line) were cultured. The plasma homocysteine was measured by using HPLC. Plasma H2S concentration and myocardial H2S production were measured with a sulfide-sensitive electrode. Confocal immunofluorescent analysis for cardiomyocytic C/EBP homologous protein (CHOP) was performed. Glucose-regulated protein 78 (GRP78), CHOP, and caspase 12 expressions by myocardial tissues and cleaved caspase 12 and p-eIF2α expressions by H9c2 cells were detected with Western blotting. The results showed that methionine overload induced HHcy, resulting in a marked cardiomyocytic ER stress, whereas endogenous production of H2S was reduced in rats with HHcy. H2S supplementation, however, decreased expressions of ER stress–associated proteins, including GRP78, CHOP, and caspase 12, by myocardial tissues in vivo. The inhibition of endogenous H2S production further enhanced cardiomyocytic ER stress, but H2S supplementation effectively antagonized the H9c2 cell CHOP, cleaved caspase 12 and p-eIF2α expressions induced by Hcy, thapsigargin, or tunicamycin in vitro. The results suggest that H2S can attenuate cardiomyocytic ER stress in HHcy-induced cardiomyocytic injury. Antioxid. Redox Signal. 12, 0000–0000.
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