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

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Abstract
Excessive nitric oxide (NO) production in cytokine-activated β cells has been implicated in β cell disruption in type 1 diabetes. β 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 β 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 Ca2+, and only agents depleting ER Ca2+ induced CHOP expression and led to apoptosis, suggesting that NO depletes ER Ca2+. Overexpression of calreticulin increased the Ca2+ 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 Ca2+, causes ER stress, and leads to apoptosis. Thus, ER Ca2+ stores are a new target of NO, and the ER stress pathway is a major mechanism of NO-mediated β cell apoptosis.