title: Gene knockout of the KCNJ8-encoded Kir6.1 K(ATP) channel imparts fatal susceptibility to endotoxemia.
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 K(ATP) 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 K(ATP) 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 K(ATP) channel, by coupling vasoreactivity with metabolic demand, provides a vital feedback element for cardiovascular tolerance in endotoxic shock.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Garvan C
authors.initials: GC
authors.lastname: Kane
authors.forename: Chen-Fuh
authors.initials: CF
authors.lastname: Lam
authors.forename: Fearghas
authors.initials: F
authors.lastname: O'Cochlain
authors.forename: Denice M
authors.initials: DM
authors.lastname: Hodgson
authors.forename: Santiago
authors.initials: S
authors.lastname: Reyes
authors.forename: Xiao-Ke
authors.initials: XK
authors.lastname: Liu
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
authors.forename: Zvonimir S
authors.initials: ZS
authors.lastname: Katusic
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000818:Animals; D001011:Aorta / Q000503:physiopathology; D003326:Coronary Circulation; D019446:Endotoxemia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006439:Hemodynamics; D066298:In Vitro Techniques; D054086:KATP Channels; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency* / Q000235:genetics*; D013686:Telemetry; D014661:Vasoconstriction; D014664:Vasodilation
chemical_list: D054086:KATP Channels; D008070:Lipopolysaccharides; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel