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

S Oyadomari1, K Takeda, M Takiguchi

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

Proceedings of the National Academy of Sciences of the United States of America
|August 30, 2001
PubMed

Insights

Excessive nitric oxide (NO) causes beta cell apoptosis in type 1 diabetes by depleting endoplasmic reticulum (ER) calcium stores, inducing ER stress and cell death. This reveals ER calcium as a novel NO target and ER stress as a key pathway in beta cell failure.

Area of Science:

  • Endocrinology
  • Cell Biology
  • Immunology

Background:

  • Cytokine-activated beta cells produce excessive nitric oxide (NO), implicated in type 1 diabetes.
  • Beta cells are highly susceptible to NO-induced apoptosis, but the underlying mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the mechanism by which nitric oxide induces apoptosis in beta cells.
  • To investigate the role of endoplasmic reticulum (ER) calcium and ER stress in NO-mediated beta cell death.

Main Methods:

  • Utilized mouse MIN6 beta cells and pancreatic islets from CHOP knockout mice.
  • Administered NO donor (SNAP) and agents affecting ER calcium levels.
  • Measured cytosolic Ca(2+), CHOP expression, and apoptosis rates.
  • Assessed the protective effect of calreticulin overexpression.

Main Results:

  • Nitric oxide (NO) donor (SNAP) induced apoptosis without significant DNA damage.
  • SNAP increased cytosolic Ca(2+) and induced CHOP expression, a marker of ER stress.
  • Agents depleting ER Ca(2+) mimicked NO's effect, inducing CHOP and apoptosis.
  • Overexpression of calreticulin protected cells against NO-induced apoptosis.
  • Pancreatic islets from CHOP knockout mice were resistant to NO-induced apoptosis.

Conclusions:

  • Nitric oxide (NO) depletes endoplasmic reticulum (ER) Ca(2+) stores, leading to ER stress and subsequent beta cell apoptosis.
  • ER Ca(2+) stores represent a novel target of NO action.
  • The ER stress pathway is a critical mechanism mediating NO-induced beta cell apoptosis, relevant to type 1 diabetes pathogenesis.

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