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PKA activity exacerbates hypoxia-induced ROS formation and hypoxic injury in PC-12 cells.

Authors
  • Gozal, Evelyne1
  • Metz, Cynthia J2
  • Dematteis, Maurice3
  • Sachleben, Leroy R Jr4
  • Schurr, Avital5
  • Rane, Madhavi J6
  • 1 Department of Pediatrics PRI, University of Louisville, School of Medicine, Louisville, KY, USA; Department of Physiology, University of Louisville, School of Medicine, Louisville, KY, USA; Department of Pharmacology & Toxicology, University of Louisville, School of Medicine, Louisville, KY, USA. Electronic address: [email protected]
  • 2 Department of Pediatrics PRI, University of Louisville, School of Medicine, Louisville, KY, USA; Department of Physiology, University of Louisville, School of Medicine, Louisville, KY, USA.
  • 3 University Hospital, Department of Addiction Medicine, Grenoble F-38043, France; Grenoble Alpes University, Faculty of Medicine, Grenoble, F-38042, France. , (France)
  • 4 Department of Pediatrics PRI, University of Louisville, School of Medicine, Louisville, KY, USA.
  • 5 Department of Anesthesiology & Perioperative Medicine, University of Louisville, School of Medicine, Louisville, KY, USA.
  • 6 Department of Medicine/Nephrology, University of Louisville, School of Medicine, Louisville, KY, USA.
Type
Published Article
Journal
Toxicology letters
Publication Date
Sep 05, 2017
Volume
279
Pages
107–114
Identifiers
DOI: 10.1016/j.toxlet.2017.07.895
PMID: 28751209
Source
Medline
Keywords
License
Unknown

Abstract

Hypoxia is a primary factor in many pathological conditions. Hypoxic cell death is commonly attributed to metabolic failure and oxidative injury. cAMP-dependent protein kinase A (PKA) is activated in hypoxia and regulates multiple enzymes of the mitochondrial electron transport chain, thus may be implicated in cellular energy depletion and hypoxia-induced cell death. Wild type (WT) PC-12 cells and PKA activity-deficient 123.7 PC-12 cells were exposed to 3, 6, 12 and 24h hypoxia (0.1% or 5% O2). Hypoxia, at 24h 0.1% O2, induced cell death and increased reactive oxygen species (ROS) in WT PC-12 cells. Despite lower ATP levels in normoxic 123.7 cells than in WT cells, hypoxia only decreased ATP levels in WT cells. However, menadione-induced oxidative stress similarly affected both cell types. While mitochondrial COX IV expression remained consistently higher in 123.7 cells, hypoxia decreased COX IV expression in both cell types. N-acetyl cysteine antioxidant treatment blocked hypoxia-induced WT cell death without preventing ATP depletion. Transient PKA catα expression in 123.7 cells partially restored hypoxia-induced ROS but did not alter ATP levels or COX IV expression. We conclude that PKA signaling contributes to hypoxic injury, by regulating oxidative stress rather than by depleting ATP levels. Therapeutic strategies targeting PKA signaling may improve cellular adaptation and recovery in hypoxic pathologies.

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