NO donor induces Nec-1-inhibitable, but RIP1-independent, necrotic cell death in pancreatic β-cells

FEBS Lett. 2011 Oct 3;585(19):3058-64. doi: 10.1016/j.febslet.2011.08.028. Epub 2011 Aug 28.

Abstract

Nitric oxide (NO) has been implicated in pancreatic β-cell death in the development of diabetes. The mechanisms underlying NO-induced β-cell death have not been clearly defined. Recently, receptor-interacting protein-1 (RIP1)-dependent necrosis, which is inhibited by necrostatin-1, an inhibitor of RIP1, has emerged as a form of regulated necrosis. Here, we show that NO donor-induced β-cell death was inhibited by necrostatin-1. Unexpectedly, however, RIP1 knockdown neither inhibited cell death nor altered the protective effects of necrostatin-1 in NO donor-treated β-cells. These results indicate that NO donor induces necrostatin-1-inhibitable necrotic β-cell death independent of RIP1. Our findings raise the possibility that NO-mediated β-cell necrosis may be a novel form of signal-regulated necrosis, which play a role in the progression of diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Death / drug effects*
  • Cell Death / physiology*
  • Cell Line
  • Cyclophilin A / metabolism
  • Gene Knockdown Techniques
  • HMGB1 Protein / metabolism
  • Humans
  • Imidazoles / metabolism*
  • Indoles / metabolism*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide Donors / pharmacology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / metabolism
  • Rats
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • S-Nitrosoglutathione / pharmacology
  • Signal Transduction / drug effects

Substances

  • HMGB1 Protein
  • Imidazoles
  • Indoles
  • Nitric Oxide Donors
  • RNA, Small Interfering
  • necrostatin-1
  • S-Nitrosoglutathione
  • Adenosine Triphosphate
  • Proto-Oncogene Proteins c-akt
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Cyclophilin A