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

Garvan C KANE; Atta BEHFAR; Roy B DYER; D. Fearghas O'Cochlain; Xiao-Ke LIU; Denice M HODGSON; Santiago REYES; Takashi MIKI; Susumu SEINO; Andre TERZIC

doi:10.1093/hmg/ddl154

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

Journal article

Peer reviewed

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

Garvan C KANE, Atta BEHFAR, Roy B DYER, D. Fearghas O'Cochlain, Xiao-Ke LIU, Denice M HODGSON, Santiago REYES, Takashi MIKI, Susumu SEINO and Andre TERZIC

Human molecular genetics, Vol.15(15), pp.2285-2297

2006

DOI: 10.1093/hmg/ddl154

PMID: 16782803

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Abstract

Heart failure is a growing epidemic, with systemic hypertension a major risk factor for development of disease. However, 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 (K ATP ) channel, predisposed to heart failure and death. Defective decoding of hypertension-induced metabolic distress signals in the K ATP channel knockout set in motion pathological calcium overload and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway. Rescue of the failing K ATP knockout phenotype was achieved by alternative control of myocardial calcium influx, bypassing uncoupled metabolic-electrical integration. The intact KCNJ11 -encoded K ATP 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.

Heart

Fundamental and applied biological sciences. Psychology

Cardiology. Vascular system

Cell membranes. Ionic channels. Membrane pores

Biological and medical sciences

Molecular and cellular biology

Genetics of eukaryotes. Biological and molecular evolution

Medical sciences

Heart failure, cardiogenic pulmonary edema, cardiac enlargement

Cell structures and functions

Details

Title: Subtitle: KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension
Creators: Garvan C KANE - Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, United States
Atta BEHFAR - Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, United States
Roy B DYER - Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, United States
D. Fearghas O'Cochlain - Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, United States
Xiao-Ke LIU - Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, United States
Denice M HODGSON - Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, United States
Santiago REYES - Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, United States
Takashi MIKI - Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
Susumu SEINO - Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
Andre TERZIC - Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, United States
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.15(15), pp.2285-2297
DOI: 10.1093/hmg/ddl154
PMID: 16782803
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: Oxford University Press
Language: English
Date published: 2006
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984094716002771

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