Premium
Gene knockout of the KCNJ8‐encoded Kir6.1 K ATP channel imparts fatal susceptibility to endotoxemia
Author(s) -
Kane Garvan C.,
Lam ChenFuh,
O'Cochlain Fearghas,
Hodgson Denice M.,
Reyes Santiago,
Liu XiaoKe,
Miki Takashi,
Seino Susumu,
Katusic Zvonimir S.,
Terzic Andre
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-6349com
Subject(s) - septic shock , sepsis , lipopolysaccharide , knockout mouse , vasodilation , gene knockout , shock (circulatory) , medicine , kir6.2 , phenotype , homeostasis , inflammation , pharmacology , immunology , biology , gene , receptor , biochemistry , protein subunit
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 Kir6.1containing K ATP channel, by coupling vasoreactivity with metabolic demand, provides a vital feedback element for cardiovascular tolerance in endotoxic shock.—Kane, G. C., Lam, C‐F., O'Cochlain, F., Hodgson, D. M., Reyes, S., Liu, X‐K., Miki, T., Seino, S., Katusic, Z. S., Terzic, A. Gene knockout of the KCNJ8encoded Kir6.1 KATP channel imparts fatal susceptibility to endotoxemia. FASEB J. 20, 2271–2280 (2006)