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

NENAD JOVANOVI, SOFIJA JOVANOVI, ALEKSANDAR JOVANOVI and ANDRE TERZIC¹

Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA

¹Correspondence: Guggenheim-7F, Mayo Clinic, 200 First St. S.W., Rochester, MN 55905, USA. E-mail: terzic.andre{at}mayo.edu

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.—Jovanovi, N., Jovanovi, S., Jovanovi, A., Terzic, A. Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca²⁺ homeostasis under metabolic stress.

Key Words: K_ATP channels • ischemia • gene therapy • potassium channel opener

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