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Objective To investigated the role of SIRT3 in ischemia-induced neuronal death due to oxygen-glucose deprivation (OGD) using an in vitro model of cerebral ischemia.Methods Normal PC12 cells and PC12 cells with PGC-1 α gene or SIRT3 gene knockdowned were used in the study.The cell viability and cytotoxicity were assessed by MTT measurement and LDH release.The generation of ATP and ROS were examined by ATP Fluorometric Assay Kit and MitoSOX Red dying respectively.The gene and protein levels of SIRT3 and PGC-1 α were assessed by PCR and western blot.Results exposure of differentiated PC12 cells to OGD for 6 h caused a marked decrease in cell viability and up regulated SIRT3.SIRT3 knockdown using short interfering RNA (siRNA) exacerbated OGD-induced injury whereas application of recombinant SIRT3 protected against OGD-induced cell death.Pre-treatment of the cells in which the SIRT3 gene was knocked down with recombinant SIRT3 before OGD partially restored cell viability and concomitantly reduced lactate dehydrogenase (LDH) release and increased ATP generation in mitochondria.Recombinant SIRT3 treatment resulted in increased expression of PGC-1 α and manganese superoxide dismutase (MnSOD).After knockdown of PGC-1 α or MnSOD, recombinant SIRT3 failed to protect against OGD-induced injury.The protein and mRNA expression of PGC-1α was down regulated following SIRT3 knockdown.The expression level of SIRT3 was reduced when the PGC-lα gene was knocked down.Conclusion SIRT3 protects PC12 cells from hypoxic injury via a mechanism that may involve PGC-1α and MnSOD.SIRT3 and PGC-1 α regulate each other under physiologic and OGD conditions, thereby partially protecting against hypoxia or ischemia.Abbreviations SIRT3, the silent information regulation 2 homolog 3 ; OGD, Oxygen-glucose deprivation; PGC-1α, Peroxisome Proliferator Activated Receptor (PPAR)-γ Co-activator 1-α ; ROS, reactive oxygen species; MnSOD, Manganese superoxide dismutase; PC12, rat pheochromocytoma; Aψ, mitochondrial membrane potential.