Oxidative stress induces caspase-independent retinal apoptosis in vitro

Apoptosis is the mode of cell death in retinitis pigmentosa (RP), a heterog eneous group of retinal degenerations. The activation of the caspase protea ses forms a pivotal step in the initiation and execution phase of apoptosis in many cells. inhibition of caspases has been reported to prevent apoptos is in many model systems. However, we demonstrate the absence of caspase ac tivation during retinal cell apoptosis in vitro which involves phosphatidyl serine (PS) externalisation, DNA nicking and cell shrinkage. In addition, z VAD-fmk, DEVD-CHO and BD-fmk, inhibitors of the caspases, were unable to al ter the characteristics or kinetics of apoptosis, implying that retinal cel l death in vitro follows a caspase-independent pathway. We have previously demonstrated the ability of reactive oxygen species (ROS) to act as mediato rs of retinal cell apoptosis in vitro as well as the ability of antioxidant s to prevent retinal cell apoptosis. Here we demonstrate the oxidative inac tivation of caspases in this model of retinal apoptosis and provide evidenc e for an oxidative stress driven cell death pathway that does not involve c aspase activity and which retains key features of apoptotic cell death. Fur thermore, our data indicates that apoptotic events such as PS exposure, DNA nicking and cell shrinkage may occur independently of caspase activity.