title: UCP2 Expression Is Increased in Pancreas From Brain-Dead Donors and Involved in Cytokine-Induced β Cells Apoptosis.
abstract: Systemic inflammation associated with brain death (BD) decreases islet yield and quality, negatively affecting outcomes of human islet transplantation. A recent study from our group showed an increased expression of uncoupling protein-2 (UCP2) in pancreas from rats with BD as compared with controls. UCP2 is located in the mitochondrial inner membrane and regulates production of reactive oxygen species and glucose-stimulated insulin secretion. It has been suggested that UCP2 also plays a role in β cell apoptosis, but these findings remain controversial.
  
  
  
  We have presently performed a case-control study to assess UCP2 expression in pancreas from BD donors (cases) and subjects who underwent pancreatectomy (controls). We next investigated the role of Ucp2 in cytokine-induced apoptosis of rat insulin-producing INS-1E cells.
  
  
  
  UCP2 gene expression was higher in pancreas from BD donors compared with controls (1.73 ± 0.93 vs 0.75 ± 0.66; fold change, P < 0.05). Ucp2 knockdown (80% at the protein and messenger RNA levels) reduced by 30% cytokine-induced apoptosis and nitric oxide production in INS-1E cells. This protection was associated with decreased expression of cleaved (activated) caspases 9 and 3, suggesting that Ucp2 knockdown interferes with cytokine triggering of the intrinsic apoptotic pathway. Moreover, both messenger RNA and protein concentrations of the antiapoptotic protein Bcl-2 were increased after Ucp2 knockdown in INS-1E cells.
  
  
  
  These data suggest that UCP2 has an apoptotic effect in β cells via regulation of the intrinsic pathway of apoptosis.
authors.affiliation: 1 Endocrine Division, Laboratory of Human Pancreatic Islet Biology, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil.2 Post-Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.3 ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Leticia A
authors.initials: LA
authors.lastname: Brondani
authors.forename: Tatiana H
authors.initials: TH
authors.lastname: Rech
authors.forename: Gabriela
authors.initials: G
authors.lastname: Boelter
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Bauer
authors.forename: Cristiane B
authors.initials: CB
authors.lastname: Leitão
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
authors.forename: Daisy
authors.initials: D
authors.lastname: Crispim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001926:Brain Death / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D016035:Pancreas Transplantation / Q000379:methods*; D010180:Pancreatectomy; D011446:Prospective Studies; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D014019:Tissue Donors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000071246:Uncoupling Protein 2 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099156:Superoxide Dismutase 2
chemical_list: D051017:Apoptosis Regulatory Proteins; D007371:Interferon-gamma; D009569:Nitric Oxide; D012333:RNA, Messenger; D013482:Superoxide Dismutase; D014409:Tumor Necrosis Factor-alpha; D000071246:Uncoupling Protein 2; D000099156:Superoxide Dismutase 2; C000604389:UCP2 protein, human; C000604391:Ucp2 protein, rat