mk-2206 and Necrosis

SC79 is a novel Akt activator. The current study tested its potential effect against oxygen and glucose deprivation (OGD)/re-oxygenation-induced myocardial cell death. We showed that SC79 activated Akt and protected H9c2 myocardial cells and primary murine myocardiocytes from OGD/re-oxygenation. Reversely, Akt inhibitor MK-2206 or Akt1 shRNA knockdown almost completely abolished SC79-mediated myocardial cytoprotection. SC79 treatment in H9c2 cells inhibited OGD/re-oxygenation-induced programmed necrosis pathway, evidenced by mitochondrial depolarization and cyclophilin D-p53-ANT-1 (adenine nucleotide translocator 1) association. Further, SC79 activated Akt downstream NF-E2-related factor 2 (NRF2) signaling to suppress OGD/re-oxygenation-induced reactive oxygen species (ROS) production. Reversely, NRF2 shRNA knockdown in H9c2 cells largely attenuated SC79-induced ROS scavenging ability and cytoprotection against OGD/re-oxygenation. Together, we conclude that activation of Akt by SC79 protects myocardial cells from OGD/re-oxygenation.

Topics: Acetates; Animals; Benzopyrans; Cells, Cultured; Cytoprotection; Enzyme Activation; Gene Expression Regulation, Enzymologic; Glucose; Heterocyclic Compounds, 3-Ring; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Necrosis; NF-E2-Related Factor 2; Oxygen; Protective Agents; Proto-Oncogene Proteins c-akt; Rats; Reactive Oxygen Species; Signal Transduction