Journal article
Gene knockout of the KCNJ8‐encoded Kir6.1 KATP channel imparts fatal susceptibility to endotoxemia
The FASEB journal, Vol.20(13), pp.2271-2280
11/2006
DOI: 10.1096/fj.06-6349com
PMID: 17077304
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 Kir6.1containing KATP 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)
Details
- Title: Subtitle
- Gene knockout of the KCNJ8‐encoded Kir6.1 KATP channel imparts fatal susceptibility to endotoxemia
- Creators
- Garvan C Kane - Mayo Clinic College of MedicineChen‐Fuh Lam - Mayo Clinic College of MedicineFearghas O'Cochlain - Mayo Clinic College of MedicineDenice M Hodgson - Mayo Clinic College of MedicineSantiago Reyes - Mayo Clinic College of MedicineXiao‐Ke Liu - Mayo Clinic College of MedicineTakashi Miki - Kobe University Graduate School of MedicineSusumu Seino - Kobe University Graduate School of MedicineZvonimir S Katusic - Mayo Clinic College of MedicineAndre Terzic - Mayo Clinic College of Medicine
- Resource Type
- Journal article
- Publication Details
- The FASEB journal, Vol.20(13), pp.2271-2280
- Publisher
- Federation of American Societies for Experimental Biology
- DOI
- 10.1096/fj.06-6349com
- PMID
- 17077304
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Number of pages
- 10
- Grant note
- Ralph Wilson Medical Research Foundation Mayo Clinic and Japanese Ministry of Education, Science, Sports, Culture and Technology National Institutes of Health Marriott Heart Disease Research Program Ted Nash Long Life Foundation
- Language
- English
- Date published
- 11/2006
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984094767902771
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