title: Cathepsin D is involved in the oxygen and glucose deprivation/reperfusion-induced apoptosis of astrocytes.
abstract: The lysosome and its associated protein cathe-psin D (Cat D) play critical roles in the pathological process of secondary damage following ischemia/reperfusion (I/R) injury. However, the roles of Cat D in I/R-exposed astrocytesremain unclear. In this study, we determined the roles of Cat D in the oxygen-glucose deprivation/reperfusion (OGD/R)-induced apoptosis of astrocytes as well as the underlying mechanisms. We found that OGD/R markedly increased cell apoptosis and the production of inflammatory cytokines, namely IL-6, tumor necrosis factor (TNF)-α and FasL in a reperfusion time‑dependent manner and their elevation peaked at 24 h after reperfusion. Moreover, the cytosolic Cat D level and Cat D activity was significantly upregulated in response to OGD/R exposure. Furthermore, OGD/R exposure gradually disrupted the innate acidic conditions of the lysosome. Exogenous TNF-α and FasL administration elevated cytosolic Cat D levels and cell apoptosis whereas TNFR1 and Fas inhibition significantly reversed these effects induced by OGD/R. Cat D overexpression enhanced cell apoptosis and the levels of apoptogenic proteins, including Bax and caspase-3, whereas Cat D siRNA transfection had an inhibitory effect on cell apoptosis and the expression of proapoptotic proteins. In addition, we observed that Cat D upregulation disrupted mitochondrial membrane potential and induced the production of reactive oxygen species. In conclusion, OGD/R injury induced the production of TNF-α, IL-6 and FasL which promoted lysosomal dysfunction and Cat D leakage into the cytoplasm. This eventually resulted in caspase‑dependent apoptosis, mitochondrial membrane potential loss and oxidative stress in astrocytes.
authors: Department of Neurology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Jianlin
authors: J
authors: Liu
authors: Department of Neurology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Lin
authors: L
authors: Yang
authors: Department of Neurology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Hongyan
authors: H
authors: Tian
authors: Department of Neurology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Qiang
authors: Q
authors: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000201:enzymology* / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism; D005947:Glucose / Q000172:deficiency*; D018836:Inflammation Mediators / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D053222:Fas Ligand Protein; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases; D002402:Cathepsin D; D005947:Glucose; D010100:Oxygen