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Titolo:
Human placenta sphingomyelinase, an exogenous acidic pH-optimum sphingomyelinase, induces oxidative stress, glutathione depletion, and apoptosis in rat hepatocytes
Autore:
Garcia-Ruiz, C; Mari, M; Morales, A; Colell, A; Ardite, E; Fernandez-Checa, JC;
Indirizzi:
Hosp Clin & Prov, Liver Unit, CSIC, Inst Invest Biomed,Inst Malalties Digest, Barcelona 08036, Spain Hosp Clin & Prov Barcelona Spain 08036 es Digest, Barcelona 08036, Spain
Titolo Testata:
HEPATOLOGY
fascicolo: 1, volume: 32, anno: 2000,
pagine: 56 - 65
SICI:
0270-9139(200007)32:1<56:HPSAEA>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; TUMOR-NECROSIS-FACTOR; MITOCHONDRIAL PERMEABILITY TRANSITION; DAUNORUBICIN-INDUCED APOPTOSIS; CERAMIDE-INDUCED APOPTOSIS; ELECTRON-TRANSPORT CHAIN; HEAVY SUBUNIT CHAIN; TRANSCRIPTIONAL REGULATION; CELL-DEATH; NEUTRAL SPHINGOMYELINASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
60
Recensione:
Indirizzi per estratti:
Indirizzo: Fernandez-Checa, JC Hosp Clin & Prov, Liver Unit, CSIC, Inst Invest Biomed,Inst Malalties Digest, Villarroel 170, Barcelona 08036, Spain Hosp Clin & Prov Villarroel 170 Barcelona Spain 08036
Citazione:
C. Garcia-Ruiz et al., "Human placenta sphingomyelinase, an exogenous acidic pH-optimum sphingomyelinase, induces oxidative stress, glutathione depletion, and apoptosis in rat hepatocytes", HEPATOLOGY, 32(1), 2000, pp. 56-65

Abstract

Ceramide has been identified as a putative lipid messenger that mediates diverse cellular processes including cell death. Since glutathione (GSH) depletion is known to sensitize cells to many cytotoxic agents and as a resultof the reported regulation of neutral sphyngomyelinase (NS-Mase) by GSH, the present study compared the role of individual SMases in the induction ofoxidative stress, regulation of cellular GSH, and apoptosis of rat hepatocytes. Exposure of cultured rat hepatocytes to exogenous Bacillus cereus sphingomyelinase (bSMase), a neutral SMase, or human placenta sphingomyelinase(hSMase), an acidic SMase (ASMase), generated similar ceramide levels in adesk-dependent manner. However, whereas bSMase increased hepatocellular GSH levels, hSMase depleted GSH stores, an effect that was prevented by monensin and mannose 6-phosphate (M-6-P), suggesting that exogenous hSMase enters hepatocytes by endocytosis and is delivered to an endosomal/lysosomal acidic compartment. Interestingly, despite the differential effect of either SMases on cell GSH levels, both bSMase and hSMase increased gamma-glutamylcysteine synthetase heavy-subunit chain (gamma-GCS-HS) mRNA levels. Consistent with these findings on GSH regulation, hSMase, but not bSMase, generated reactive oxygen species (ROS), being accompanied by mitochondrial depolarization, suggesting that hSMase targeted mitochondria, leading to oxidative stress. Accordingly, hepatocytes displayed a selective sensitivity to hSMasein contrast to bSMase exposure, and depletion of GSH stores enhanced susceptibility to hSMase as a result of potentiation of ROS formation and caspase 3 activation. Thus, these findings reveal the ability of ASMase to induceoxidative stress as a result of the targeting of mitochondria, and that GSH depletion sensitizes hepatocytes to the ASMase-induced apoptosis.

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Documento generato il 23/01/20 alle ore 03:39:20