Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca2+ homeostasis under metabolic stress

Nenad Jovanović, Sofija Jovanović, Aleksandar Jovanović, Andre Terzic

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Metabolic injury is a complex process affecting various tissues, with intracellular Ca2+ loading recognized as a common precipitating event leading to cell death. We have recently observed that cells overexpressing recombinant ATP-sensitive K+ (K(ATP)) channel subunits may acquire resistance against metabolic stress. To examine whether, under metabolic challenge, intracellular Ca2+ homeostasis can be maintained by an activator of channel proteins, we delivered Kir6.2 and SUR2A genes, which encode K(ATP) channel subunits, into a somatic cell line lacking native K(ATP) channels. Hypoxia-reoxygenation was simulated by application and removal of the mitochondrial poison 2,4 dinitrophenol. Under such metabolic stress, Ca2+ loading was induced by Ca2+ influx during hypoxia and release of Ca2+ from intracellular stores during reoxygenation. Delivery of Kir6.2/SUR2A genes, in conjunction with the K(ATP) channel activator pinacidil, prevented intracellular Ca2+ loading irrespective of whether the channel opener was applied throughout the duration of hypoxia-reoxygenation or transiently during the hypoxic or reoxygenation stage. In all stages of injury, the effect of pinacidil was inhibited by the selective antagonist of K(ATP) channel, 5-hydroxydecanoate. The present study provides evidence that combined use of gene delivery and pharmacological targeting of recombinant proteins can handle intracellular Ca2+ homeostasis under hypoxia- reoxygenation irrespective of the stage of the metabolic insult.

Original languageEnglish (US)
Pages (from-to)923-929
Number of pages7
JournalFASEB Journal
Volume13
Issue number8
DOIs
StatePublished - 1999

Keywords

  • Gene therapy
  • Ischemia
  • K(ATP) channels
  • Potassium channel opener

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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