H2S, endoplasmic reticulum stress, and apoptosis of insulin-secreting beta cells.
Cystathionine gamma-lyase (CSE) is a key enzyme in the trans-sulfuration pathway, which uses L-cysteine to produce hydrogen sulfide (H2S). Functional changes of pancreatic beta cells induced by endogenous H2S have been reported, but the effect of the CSE/H2S system on pancreatic beta cell survival has not been known. In this study, we demonstrate that H2Sat physiologically relevant concentrations induced apoptosis of INS-1E cells, an insulin-secreting beta cell line. Transfection of INS-1E cells with a recombinant defective adenovirus containing the CSE gene (Ad-CSE) resulted in a significant increase in CSE expression and H2S production. Ad-CSE transfection also stimulated apoptosis. The other two end products of CSE-catalyzed enzymatic reaction, ammonium and pyruvate, had no effects on INS-1E cell apoptosis, indicating that overexpression of CSE may stimulate INS-1E cell apoptosis via increased endogenous production of H2S. Both exogenous H2S (100 microM) and Ad-CSE transfection inhibited ERK1/2 but activated p38 MAPK. Interestingly, BiP and CHOP, two indicators of endoplasmic reticulum (ER) stress, were up-regulated in H2S-and CSE-mediated apoptosis in INS-1E cells. After suppressing CHOP mRNA expression, H2S-induced apoptosis of INS-1E cells was significantly decreased. Inhibition of p38 MAPK, but not of ERK1/2, inhibited the expression of BiP and CHOP and decreased H2S-stimulated apoptosis, suggesting that p38 MAPK activation functions upstream of ER stress to initiate H2S-induced apoptosis. It is concluded that H2S induces apoptosis of insulin-secreting beta cells by enhancing ER stress via p38 MAPK activation. Our findings may help unmask a novel role of CSE/H2S system in regulating pancreatic functions under physiological condition and in diabetes.
Yang
Guangdong
G
Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
Yang
Wei
W
Wu
Lingyun
L
Wang
Rui
R
D000256:Adenoviridae; D000393:Air Pollutants / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003542:Cystathionine gamma-Lyase / Q000096:biosynthesis* / Q000235:genetics; D003545:Cysteine / Q000378:metabolism; D003920:Diabetes Mellitus / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006360:Heat-Shock Proteins / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism* / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D051381:Rats; D013312:Stress, Physiological / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051742:Transcription Factor CHOP / Q000378:metabolism; D014161:Transduction, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
D000393:Air Pollutants; D003542:Cystathionine gamma-Lyase; D003545:Cysteine; D006360:Heat-Shock Proteins; D006862:Hydrogen Sulfide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018832:Molecular Chaperones; D051742:Transcription Factor CHOP; D048051:p38 Mitogen-Activated Protein Kinases; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP