Gene knockout of the KCNJ8-encoded Kir6.1 KATP channel imparts fatal susceptibility to endotoxemia

Garvan C. Kane, Chen Fuh Lam, Fearghas O'Cochlain, Denice M. Hodgson, Santiago Reyes, Xiao Ke Liu, Takashi Miki, Susumu Seino, Zvonimir S. Katusic, Andre Terzic

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Sepsis, the systemic inflammatory response to infection, imposes a high demand for bodily adaptation, with the cardiovascular response a key determinant of outcome. The homeostatic elements that secure cardiac tolerance in the setting of the sepsis syndrome are poorly understood. Here, in a model of acute septic shock induced by endotoxin challenge with Escherichia coli lipopolysaccharide (LPS), knockout of the KCNJ8 gene encoding the vascular Kir6.1 KATP channel pore predisposed to an early and profound survival disadvantage. The exaggerated susceptibility provoked by disruption of this stress-responsive sensor of cellular metabolism was linked to progressive deterioration in cardiac activity, ischemic myocardial damage, and contractile dysfunction. Deletion of KCNJ8 blunted the responsiveness of coronary vessels to cytokine- or metabolic-mediated vasodilation necessary to support myocardial perfusion in the wild-type (WT), creating a deficit in adaptive response in the Kir6.1 knockout. Application of a KATP channel opener drug improved survival in the endotoxic WT but had no effect in the Kir6.1 knockout. Restoration of the dilatory capacity of coronary vessels was required to rescue the Kir6.1 knockout phenotype and reverse survival disadvantage in lethal endotoxemia. Thus, the Kir6.1-containing KATP channel, by coupling vasoreactivity with metabolic demand, provides a vital feedback element for cardiovascular tolerance in endotoxic shock.

Original languageEnglish (US)
Pages (from-to)2271-2280
Number of pages10
JournalFASEB Journal
Volume20
Issue number13
DOIs
StatePublished - Nov 1 2006

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Keywords

  • ATP-sensitive K channel
  • Kir6.1
  • Metabolism
  • Sepsis
  • Septic shock
  • Vasodilation

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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