Journal article
Cellular remodeling in heart failure disrupts KATP channel-dependent stress tolerance
The EMBO journal, Vol.22(8), pp.1732-1742
04/15/2003
DOI: 10.1093/emboj/cdg192
PMCID: PMC154482
PMID: 12682006
Abstract
ATP-sensitive potassium (K
ATP
) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K
ATP
channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor α induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K
ATP
channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K
ATP
channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by K
ATP
channel openers. Thus, disease-induced K
ATP
channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy.
Details
- Title: Subtitle
- Cellular remodeling in heart failure disrupts KATP channel-dependent stress tolerance
- Creators
- Denice M Hodgson - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental TherapeuticsLeonid V Zingman - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental TherapeuticsGarvan C Kane - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental TherapeuticsCarmen Perez-Terzic - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental TherapeuticsMartin Bienengraeber - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental TherapeuticsCevher Ozcan - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental TherapeuticsRichard J Gumina - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental TherapeuticsDarko Pucar - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental TherapeuticsFergus O’Coclain - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental TherapeuticsDouglas L Mann - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental TherapeuticsAlexey E Alekseev - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental TherapeuticsAndre Terzic - Division of Cardiovascular Diseases, Department of Medicine, Department of Molecular Pharmacology and Experimental Therapeutics
- Resource Type
- Journal article
- Publication Details
- The EMBO journal, Vol.22(8), pp.1732-1742
- Publisher
- Oxford University Press
- DOI
- 10.1093/emboj/cdg192
- PMID
- 12682006
- PMCID
- PMC154482
- ISSN
- 0261-4189
- eISSN
- 1460-2075
- Language
- English
- Date published
- 04/15/2003
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984094570902771
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