Differential modulation of 7-ketocholesterol toxicity against PC12 cells by calmodulin antagonists and Ca2+ channel blockers.
The present study assessed the influence of intracellular Ca2+ and calmodulin against the neurotoxicity of oxysterol 7-ketocholesterol in relation to the mitochondria-mediated cell death process and oxidative stress in PC12 cells. Calmodulin antagonists calmidazolium and W-7 prevented the 7-ketocholesterol-induced mitochondrial damage, leading to caspase-3 activation and cell death, whereas Ca2+ channel blocker nicardipine, mitochondrial Ca2+ uptake inhibitor ruthenium red, and cell permeable Ca2+ chelator BAPTA-AM did not reduce it. Exposure of PC12 cells to 7-ketocholesterol caused elevation of intracellular Ca2+ levels. Unlike cell injury, calmodulin antagonists, nicardipine, and BAPTA-AM prevented the 7-ketocholesterol-induced elevations of intracellular Ca2+ levels. The results show that the cytotoxicity of 7-ketocholesterol seems to be modulated by calmodulin rather than changes in intracellular Ca2+ levels. Calmodulin antagonists may prevent the cytotoxicity of 7-ketocholesterol by suppressing the mitochondrial permeability transition formation, which is associated with the increased formation of reactive oxygen species and the depletion of GSH.
Lee
Chung Soo
CS
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea. leecs@cau.ac.kr
Park
Woo Jae
WJ
Han
Eun Sook
ES
Bang
Hyoweon
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000502:physiology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007653:Ketocholesterols / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051336:Mitochondrial Membranes / Q000187:drug effects; D009529:Nicardipine / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D012430:Ruthenium Red / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002147:Calmodulin; D007093:Imidazoles; D007653:Ketocholesterols; D013449:Sulfonamides; D012430:Ruthenium Red; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C031938:calmidazolium; D004533:Egtazic Acid; C017967:W 7; D014700:Verapamil; D009529:Nicardipine; C003001:7-ketocholesterol; D002118:Calcium