Abstract 147: δ-opioid Receptor Activation Increases Nrf2 Nuclear Translocation And Stabilizes Mitochondrial Membrane Potential Of Hypoxic Cells

Conditions that limit O2 supply for a prolonged period lead to cardiac injury. However, current strategies against hypoxic cardiac injury are limited in clinical settings. It is of utmost importance to find novel clues for protecting cells from hypoxic injury. Our work has recently shown that δ-opioid receptor (DOR) activation strongly regulates microRNA expression in the heart exposed to prolonged hypoxia, suggesting a role of DOR in cardiac adaptation to hypoxic stress. To further determine DOR's action on cell survival under hypoxia and the underlying mechanisms, we exposed HEK293t cells to hypoxia for a prolonged period and then investigated cellular viability and changes in mitochondrial membrane potential and the nuclear factor erythroid 2-related factor 2 (Nrf2), which are thought to be involved in the regulation of cell survival under hypoxia. Our data show that prolonged hypoxia (0.5% of O2 for 16-48 hours) caused serious cellular injury. DOR activation with UFP-512, a potent and specific DOR agonist, prevented the collapse of mitochondrial membrane potential and markedly attenuated cell injury in the hypoxic condition. The DOR-mediated protection was largely reversed by DOR antagonism with naltrindole. Furthermore, we observed that DOR activation increased Nrf2 translocation from cytoplasm to nucleus. The DOR-mediated cytoprotection was largely abolished by the "knock-down" of Nrf2. Our results suggest that DOR activation increases Nrf2 nuclear translocation and stabilizes mitochondrial membrane potential during the process of cellular protection against hypoxic stress.

SC and TC are equal contributors.

Supported by HD-034852, AT-004422, NSFC 81060096 and 81260204.