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J. Biol. Chem., Vol. 282, Issue 22, 16567-16576, June 1, 2007

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H₂S, Endoplasmic Reticulum Stress, and Apoptosis of Insulin-secreting Beta Cells^*

Guangdong Yang¹, Wei Yang², Lingyun Wu³, and Rui Wang^¶4

From the Departments of Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5 and the ^¶Department of Biology, Faculty of Science and Environmental Studies, Lakehead University, Thunder Bay, Ontario P7B 5E1, Canada

Cystathionine -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 µM) 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.

Received for publication, January 22, 2007 , and in revised form, March 23, 2007.

^* This work was supported in part by Natural Sciences and Engineering Research Council of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a research fellowship award from the Heart and Stroke Foundation of Canada.

² Supported by a postdoctoral fellowship from GREAT training program of Canadian Institutes of Health Research/Heart and Stroke Foundation of Canada.

³ Supported by a New Investigator Award of Canadian Institutes of Health Research.

⁴ To whom correspondence should be addressed: Office of Vice President (Research), Lakehead University, 955 Oliver Rd., Thunder Bay, Ontario P7B 5E1, Canada. Tel.: 807-343-8180; Fax: 807-346-7749; E-mail: rwang{at}lakeheadu.ca.

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