Nitric Oxide Induces Apoptosis Via Ca²⁺-Dependent Processes in the Pancreatic β-cell Line MIN6

Abstract

An excessive production of nitric oxide (NO) in response to cytokines has been shown to be the major cause of the destruction of islet β-cells associated with type 1 (insulin-dependent) diabetes mellitus. The NO-induced β-cell death is the typical apoptosis. In the present study, we show evidcnce that supports a tight link between NO, Ca²⁺, protease and apoptosis in β-cells. Three different NO donors, SNAP, NOR3 and NOC7, induced apoptosis in a β-cell line, MIN6 cells, in a concentration-dependent manner. SNAP at 200 μM increased cytosolic Ca²⁺ concentration ([Ca²⁺]_i) and induced apoptosis. The SNAP-induced apoptosis was blocked by a Ca²⁺ chelator, BAPTA-AM, and by an inhibitor of a Ca²⁺-dependent protease, calpain. In conclusion, an excessive NO production induces apoptosis, wherein an increase in [Ca²⁺]_i and resultant activation of calpain play a key role.