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THE ROLE OF PROTEIN KINASE A IN HYPOXIA-INDUCED PC-12 CELL DEATH Cynthia Jayne Miller July 1, 2008 Hypoxia is characterized by an inadequate oxygen supply to the tissues in proportion to their metabolic needs, and is a primary factor in traumatic CNS injury, strokes, cardiopulmonary diseases, and obstructive sleep apnea. The cAMP-dependent protein kinase (PKA) has been attributed a role as an antiapoptotic kinase as well as a pro-apoptotic signal. Thus the role of PKA in hypoxia-induced cell survival is currently unclear. We show here that hypoxia induces cell death in WT PC-12 cells, pheochromocytoma cells used as a model of the oxygen-sensitive carotid body glomus cells. The onset of cell death following 24 hours of severe, sustained hypoxia also correlated with an increase in oxidative stress and a drop in ATP levels. Inactivation of PKA in the 123.7 PC-12 cell line prevented the hypoxiainduced ROS surge, energy depletion, and cell death. PKA activity thus contributes to hypoxia~induced cell death in WT cells via enhanced ROS production and energy depletion, but was not shown to playa role in the regulation of cellular antioxidant mechanisms.

The role of protein kinase A in hypoxia-induced PC-12 cell death.