Acquired resistance of a mammalian cell line to hypoxia-reoxygenation through cotransfection of Kir6.2 and SUR1 clones

Aleksandar Jovanovic, Sofija Jovanovic, Antonio J. Carrasco, Andre Terzic

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Reoxygenation after transient hypoxia is a common clinical condition that often causes greater tissue damage than persistent hypoxia itself. This warrants the development of a means to protect cells against hypoxia- reoxygenation injury. Adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channels have been proposed to play an essential role in the mechanisms of endogenous cellular protection. Thus far, however, K(ATP) channel proteins have not been exploited to generate an injury-resistant cellular phenotype by delivering K(ATP) channel genes into injury-prone cells. A first step in this direction is the evaluation of the outcome of transferring genes encoding K(ATP), channels into a K(ATP) channel-deficient cell type exposed to metabolic stress. Untransfected COS-7 monkey kidney cells, which natively lack K(ATP) channels, were found to be vulnerable to hypoxia-reoxygenation injury, which induced cytosolic Ca2+ loading, as measured by digital epifluorescent imaging. COS-7 cells cotransfected with K(ATP) channel genes, Kir6.2 and SUR1, gained resistance to hypoxia-reoxygenation. This acquired resistance was abolished by glyburide; the K(ATP) channel antagonist. We have previously shown that Kir6.2 and SUR1 physically associate to form a functional K(ATP) channel, not reconstituted by either of the subunits alone. Transfection with individual channel subunits Kir6.2 or SUR1, failed to produce resistance to hypoxia-reoxygenation induced Ca2+ loading. This is a first demonstration that transfer of K(ATP) channel subunits can generate an injury-resistant cellular phenotype. The findings from this study may, thus, provide a framework for future therapeutic strategies based on gene delivery of K(ATP) channel subunits in cells and tissues vulnerable to hypoxia- reoxygenation insults.

Original languageEnglish (US)
Pages (from-to)1101-1107
Number of pages7
JournalLaboratory Investigation
Volume78
Issue number9
StatePublished - Sep 1 1998

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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