UCP2 Expression Is Increased in Pancreas From Brain-Dead Donors and Involved in Cytokine-Induced β Cells Apoptosis

Transplantation. 2017 Mar;101(3):e59-e67. doi: 10.1097/TP.0000000000001292.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: These data suggest that UCP2 has an apoptotic effect in β cells via regulation of the intrinsic pathway of apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Brain Death / metabolism*
  • Brain Death / pathology
  • Case-Control Studies
  • Cell Line
  • Humans
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Interferon-gamma / pharmacology*
  • Nitric Oxide / metabolism
  • Pancreas Transplantation / methods*
  • Pancreatectomy
  • Prospective Studies
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Signal Transduction / drug effects*
  • Superoxide Dismutase / metabolism
  • Time Factors
  • Tissue Donors*
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Uncoupling Protein 2 / genetics
  • Uncoupling Protein 2 / metabolism*
  • Up-Regulation

Substances

  • Apoptosis Regulatory Proteins
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • UCP2 protein, human
  • Ucp2 protein, rat
  • Uncoupling Protein 2
  • Nitric Oxide
  • Interferon-gamma
  • Superoxide Dismutase
  • superoxide dismutase 2