Sustained elevation of intracellular cGMP causes oxidative stress triggering calpain-mediated apoptosis in photoreceptor degeneration.
Sustained elevation in cGMP and a concomitant increase in intracellular Ca(2+) levels in the rd1 photoreceptors are followed by a rapid loss of photoreceptors. In a murine-derived photoreceptor cell line, 661W, treated with the phosphodiesterase inhibitor IBMX or the cyclic GMP-gated channel agonist 8-bromo-cGMP, it was previously found that the induced cell death was mediated by calpain and caspase-3. Because oxidative stress is a common product of ionic imbalance or elevated Ca(2+), we tested the role of oxidative stress in cGMP-induced photoreceptor cell death. In the rd1 mouse retina, oxidative stress was found to precede calpain and caspase-3 activation. In 661W cells, the increase in intracellular cGMP and Ca(2+) resulted in the generation of reactive oxygen species (ROS), the activation of oxidative stress enzymes, and the activation of calpain, followed by apoptosis mediated by the effector caspase-3. All these events, including calpain activation, were ameliorated by docosahexanoic acid (DHA). The cell-permeable inhibitor of calpain, SJA6017, while inhibiting cell death, had no effect on the generation of oxidative stress. These results establish a central role for oxidative stress in cGMP-induced cell death and suggest a ROS-mediated sequential activation of signal transduction events, which provide targets for future treatment strategies.
Sharma
Ashish K
AK
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Rohrer
Bärbel
B
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D006152:Cyclic GMP / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018384:Oxidative Stress; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology
D010726:Phosphodiesterase Inhibitors; D017382:Reactive Oxygen Species; D004281:Docosahexaenoic Acids; D045304:Cytochromes c; D002374:Catalase; D005979:Glutathione Peroxidase; D002154:Calpain; D053148:Caspase 3; D006152:Cyclic GMP; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine