1. H2S, Endoplasmic Reticulum Stress, and Apoptosis of Insulin-secreting Beta Cells
- Author
-
Rui Wang, Wei Yang, Guangdong Yang, and Lingyun Wu
- Subjects
Cell Survival ,p38 mitogen-activated protein kinases ,Apoptosis ,Biology ,CHOP ,Endoplasmic Reticulum ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Adenoviridae ,Stress, Physiological ,Transduction, Genetic ,Cell Line, Tumor ,Insulin-Secreting Cells ,parasitic diseases ,Diabetes Mellitus ,Animals ,Cysteine ,Hydrogen Sulfide ,Molecular Biology ,Heat-Shock Proteins ,Mitogen-Activated Protein Kinase 1 ,Air Pollutants ,Mitogen-Activated Protein Kinase 3 ,Endoplasmic reticulum ,Cystathionine gamma-Lyase ,Cell Biology ,Transfection ,equipment and supplies ,Rats ,Cell biology ,Gene Expression Regulation ,Cell culture ,Unfolded protein response ,Beta cell ,Transcription Factor CHOP ,Molecular Chaperones - Abstract
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.
- Published
- 2007