Format

Send to:

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10845-50. Epub 2001 Aug 28.

Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway.

Author information

  • 1Department of Molecular Genetics, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan.

Abstract

Excessive nitric oxide (NO) production in cytokine-activated beta cells has been implicated in beta cell disruption in type 1 diabetes. beta cells are very vulnerable to NO-induced apoptosis. However, the mechanism underlying this phenomenon is unclear. Low concentrations of NO that lead to apoptosis apparently do not cause severe DNA damage in mouse MIN6 beta cells. CHOP, a C/EBP homologous protein that is induced by endoplasmic reticulum (ER) stress and plays a role in growth arrest and cell death, was induced by a NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP). SNAP increased cytosolic Ca(2+), and only agents depleting ER Ca(2+) induced CHOP expression and led to apoptosis, suggesting that NO depletes ER Ca(2+). Overexpression of calreticulin increased the Ca(2+) content of ER and afforded protection to cells against NO-mediated apoptosis. Furthermore, pancreatic islets from CHOP knockout mice showed resistance to NO. We conclude that NO depletes ER Ca(2+), causes ER stress, and leads to apoptosis. Thus, ER Ca(2+) stores are a new target of NO, and the ER stress pathway is a major mechanism of NO-mediated beta cell apoptosis.

PMID:
11526215
[PubMed - indexed for MEDLINE]
PMCID:
PMC58562
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk