| Gene knockout of the KCNJ8-encoded Kir6.1 K(ATP) channel imparts fatal susceptibility to endotoxemia. | |
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MedLine Citation:
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PMID: 17077304 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology Volume: 20 ISSN: 1530-6860 ISO Abbreviation: FASEB J. Publication Date: 2006 Nov |
Date Detail:
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Created Date: 2006-11-01 Completed Date: 2006-11-27 Revised Date: 2012-02-15 |
Medline Journal Info:
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Nlm Unique ID: 8804484 Medline TA: FASEB J Country: United States |
Other Details:
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Languages: eng Pagination: 2271-80 Citation Subset: IM |
Affiliation:
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Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aorta / physiopathology Coronary Circulation Endotoxemia / genetics*, pathology, physiopathology Genetic Predisposition to Disease Hemodynamics KATP Channels Lipopolysaccharides / toxicity Mice Mice, Inbred C57BL Mice, Knockout Myocardium / pathology Potassium Channels, Inwardly Rectifying / deficiency*, genetics* Telemetry Vasoconstriction Vasodilation |
| Chemical | |
Reg. No./Substance:
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0/KATP Channels; 0/Lipopolysaccharides; 0/Potassium Channels, Inwardly Rectifying; 0/uK-ATP-1 potassium channel |
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