Document Detail

Transcription factor CHF1/Hey2 regulates EC coupling and heart failure in mice through regulation of FKBP12.6.
MedLine Citation:
PMID:  22408025     Owner:  NLM     Status:  MEDLINE    
Heart failure is a leading cause of morbidity and mortality in Western society. The cardiovascular transcription factor CHF1/Hey2 has been linked to experimental heart failure in mice, but the mechanisms by which it regulates myocardial function remain incompletely understood. The objective of this study was to determine how CHF1/Hey2 affects development of heart failure through examination of contractility in a myocardial knockout mouse model. We generated myocardial-specific knockout mice. At baseline, cardiac function was normal, but, after aortic banding, the conditional knockout mice demonstrated a greater increase in ventricular weight-to-body weight ratio compared with control mice (5.526 vs. 4.664 mg/g) and a significantly decreased ejection fraction (47.8 vs. 72.0% control). Isolated cardiac myocytes from these mice showed decreased calcium transients and fractional shortening after electrical stimulation. To determine the molecular basis for these alterations in excitation-contraction coupling, we first measured total sarcoplasmic reticulum calcium stores and calcium-dependent force generation in isolated muscle fibers, which were normal, suggesting a defect in calcium cycling. Analysis of gene expression demonstrated normal expression of most genes known to be involved in myocardial calcium cycling, with the exception of the ryanodine receptor binding protein FKBP12.6, which was expressed at increased levels in the conditional knockout hearts. Treatment of the isolated knockout myocytes with FK506, which inhibits the association of FKBP12.6 with the ryanodine receptor, restored contractile function. These findings demonstrate that conditional deletion of CHF1/Hey2 in the myocardium leads to abnormalities in calcium handling mediated by FKBP12.6 that predispose to pressure overload-induced heart failure.
Yonggang Liu; F Steven Korte; Farid Moussavi-Harami; Man Yu; Maria Razumova; Michael Regnier; Michael T Chin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-03-09
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  302     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-03     Completed Date:  2012-07-03     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1860-70     Citation Subset:  IM    
Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
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MeSH Terms
Basic Helix-Loop-Helix Transcription Factors / deficiency,  genetics,  physiology*
Calcium / metabolism
Cardiomegaly / physiopathology
Cells, Cultured
Disease Models, Animal
Heart Conduction System / physiology*
Heart Failure / physiopathology*
Mice, Inbred C57BL
Mice, Knockout
Myocardial Contraction / drug effects,  physiology*
Myocytes, Cardiac / drug effects
Repressor Proteins / deficiency,  genetics,  physiology*
Ryanodine Receptor Calcium Release Channel / drug effects
Sarcoplasmic Reticulum / metabolism
Stroke Volume / physiology
Tacrolimus / pharmacology
Tacrolimus Binding Proteins / physiology*
Grant Support
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/FKBP12.6 protein, mouse; 0/Hey2 protein, mouse; 0/Repressor Proteins; 0/Ryanodine Receptor Calcium Release Channel; 109581-93-3/Tacrolimus; 7440-70-2/Calcium; EC 5.2.1.-/Tacrolimus Binding Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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