Hydrogen Sulfide Ameliorates Myocardial Injury Caused by Sepsis Through Suppressing ROS-Mediated Endoplasmic Reticulum Stress

ZHAO Yu-han, CAO Guo-dong, GUO Li-chun, CHENG Qing-hong

Abstract

To investigate the effect of hydrogen sulfide (H2S) on reactive oxygen species (ROS)-mediated endoplasmic reticulum stress in myocardial injury caused by sepsis.  Methods  A sepsis model was induced in Sprague-Dawley (SD) rats by cecal ligation and puncture (CLP). The rats were randomly divided into sham operation (sham) group, sepsis (CLP) group, and sepsis+sodium hydrosulfide (NaHS) (CLP+NaHS) group. The left ventricular function of the rats was observed with echocardiography and their plasma H2S levels were measured. Lactate dehydrogenase (LDH), malondialdehyde (MDA), glutathione (GSH) levels were measured and HE staining was done to evaluate the level of myocardial oxidative stress in rats. HE staining was done to observe the morphological changes of rat myocardium, and transmission electron microscope was used to observe the ultrastructure of myocardial mitochondria. Western blot was done to examine changes in the expression of two endogenous hydrogen sulfide synthases, cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfur transferase (3-MST), and changes in the expression of endoplasmic reticulum stress (ERS) marker proteins, including phosphorylated (p) protein kinase R-like endoplasmic reticulum kinase (p-PERK), p-eukaryotic translation initiation factor 2α (p-eIF2α), p-inositol requires enzyme 1α (IRE1α), recombinant activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). TUNEL staining was performed to observe the changes of cardiomyocyte apoptosis in rats.   Results  Left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVFS) and plasma H2S decreased in septic rats (P<0.05). Plasma H2S exhibited linear correlation with LVEF and LVFS (r2=0.62 and r2=0.64, all P<0.05). The ROS levels were significantly elevated in rats of the CLP group. In addition, these rats showed increased level of LDH (P<0.05), increased expression of MDA (P<0.05), and decreased expression of GSH (P<0.05). Inflammatory cell infiltration and cardiomyocyte edema were observed in HE staining. Transmission electron microscopic observation revealed significant mitochondrial damage, observable mitochondrial edema, and cristae structure dissolution. The Western blot results showed that the expression levels of CSE and 3-MST decreased (P<0.05), while the ERS marker proteins, including p-PERK, p-eIF2, IRE1α, ATF4, and CHOP, were expressed at increased levels (P<0.05). TUNEL staining showed significant increase of apoptosis in cardiomyocytes (P<0.05). After NaHS treatment, LVEF and LVFS increased (P<0.05) and plasma H2S increased in septic rats (P<0.05). Myocardial oxidative stress levels decreased. HE staining and transmission electron microscopy showed improved myocardial morphology. Mitochondrial damage was reduced and CSE and 3-MST levels were significantly increased (P<0.05). The expression of p-PERK, p-eIF2α, p-IRE1α, and CHOP proteins decreased (P<0.05). A decrease in cardiomyocyte apoptosis levels was observed by TUNEL staining (P<0.05).   Conclusion  H2S reduces septic cardiomyocyte apoptosis by inhibiting ROS-mediated ERS, thereby improving myocardial dysfunction in sepsis.

 

Keywords: Sepsis, Myocardial injury, Apoptosis, Endoplasmic reticulum stress, Hydrogen sulfide

 

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