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Human Molecular Genetics Advance Access published online on June 16, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl154
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© 2006 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received April 11, 2006
Revised June 13, 2006
Accepted June 13, 2006

Article

KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension

Garvan C. Kane 1, Atta Behfar 1, Roy B. Dyer 1, D. Fearghas O'Cochlain 1, Xiao-Ke Liu 1, Denice M. Hodgson 1, Santiago Reyes 1, Takashi Miki 2, Susumu Seino 2, and Andre Terzic 3 *

1 Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
2 Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
3 Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

* To whom correspondence should be addressed.
Andre Terzic, E-mail: terzic.andre{at}mayo.edu


  Abstract

Heart failure is a growing epidemic, with systemic hypertension a major risk factor for development of disease. Yet, the molecular determinants that prevent the transition from a state of hypertensive load to that of overt cardiac failure remain largely unknown. Here in experimental hypertension, knockout of the KCNJ11 gene, encoding the Kir6.2 pore-forming subunit of the sarcolemmal ATP-sensitive potassium (KATP) channel, predisposed to heart failure and death. Defective decoding of hypertension-induced metabolic distress signals in the KATP channel knockout set in motion pathologic calcium overload, and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway. Rescue of the failing KATP knockout phenotype was achieved by alternative control of myocardial calcium influx, bypassing uncoupled metabolic-electrical integration. The intact KCNJ11-encoded KATP channel is thus a required safety element preventing hypertension-induced heart failure, with channel dysfunction a molecular substrate for stress-associated channelopathy in cardiovascular disease.


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