Protein kinase C delta cleavage initiates an aberrant signal transduction pathway after cardiac arrest and oxygen glucose deprivation

Ami P. Raval, Kunjan R. Dave, Ricardo Prado, Laurence M. Katz, Raul Busto, Thomas J. Sick, Myron D. Ginsberg, Daria Mochly-Rosen, Miguel A. Pérez-Pinzón

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Protein kinase C (PKC) isozymes have been known to mediate a variety of complex and diverse cellular functions. δPKC has been implicated in mediating apoptosis. Using two models of cerebral ischemia, cardiac arrest in rats and oxygen glucose deprivation (OGD) in organotypic hippocampal slices, we tested whether an ischemic insult promoted δPKC cleavage during the reperfusion and whether the upstream pathway involved release of cytochrome c and caspase 3 cleavage. We showed that cardiac arrest/OGD significantly enhanced δPKC translocation and increased its cleavage at 3 h of reperfusion. Since δPKC is one of the substrates for caspase 3, we next determined caspase 3 activation after cardiac arrest and OGD. The maximum decrease in levels of procaspase 3 was observed at 3 h of reperfusion after cardiac arrest and OGD. We also determined cytochrome c release, since it is upstream of caspase 3 activation. Cytochrome c in cytosol increased at 1 h of reperfusion after cardiac arrest/OGD. Inhibition of either δPKC/caspase 3 during OGD and early reperfusion resulted in neuroprotection in CA1 region of hippocampus. Our results support the deleterious role of δPKC in reperfusion injury. We propose that early cytochrome c release and caspase 3 activation promote δPKC translocation/cleavage.

Original languageEnglish (US)
Pages (from-to)730-741
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume25
Issue number6
DOIs
StatePublished - Jun 2005

Keywords

  • Caspase 3
  • Cytochrome c
  • Global ischemia
  • Hippocampus
  • Neurodegeneration
  • Organotypic slice cultures

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

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