Role of ORP150 in hypoxia/ischemia-induced neuronal cell death

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The role of 150-kDa oxygen regulated protein (ORP150) in hypoxia/ischemia-induced neuronal death was investigated. In cultured rat cortical neurons, cell death was accelerated by hypoxia with no obvious induction of ORP150, whereas cell viability was well maintained in cultured astrocytes with marked induction of ORP150. Adenovirus-mediated overexpression of ORP150 in cortical neurons resulted in the marked increase of ORP150 accompanied in parallel with restoration of cell viability under hypoxia. The introduction of antisense structure of ORP150 into astrocytes inhibited the induction of ORP150 under hypoxic condition and resulted in decreased cell viability. The tolerance of neurons given by ORP150 overexpression was observed in the hypoxic environment, but not in other apoptotic paradigm caused by heat shock or hydrogen peroxide. In vivo experiments revealed that the induction of ORP150 was observed in neurons as well as in astrocytes after the unilateral occlusion of the middle cerebral artery (MCA), as detected by immunohistochemical and in-situ hybridization analysis. Furthermore, to further explore the role of ORP150 in regulation of ischemic/hypoxic neuronal death in vivo, we generated transgenic mice expressing ORP150 under control of PDGF promoter, which forced expression uniquely in neurons. Profound protection against hypoxic insults in vitro and major decrease in infarct volume after permanent MCA occlusion was observed in ORP150 transgnic mice. These data suggest that ORP150 may play a protective role in neurons against ischemic/hypoxic insults.