Transcription factor CHF1/Hey2 regulates EC coupling and heart failure in mice through regulation of FKBP12.6.

Abstract

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.

• Authors: Yonggang Liu, F Steven Korte, Farid Moussavi-Harami, Man Yu, Maria Razumova, Michael Regnier, Michael T Chin
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 302 Issue 9 Pg. H1860-70 (May 01 2012) ISSN: 1522-1539 [Electronic] United States
• PMID: 22408025 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• FKBP12.6 protein, mouse
• Hey2 protein, mouse
• Repressor Proteins
• Ryanodine Receptor Calcium Release Channel
• Tacrolimus Binding Proteins
• Calcium
• Tacrolimus

Topics

• Animals
• 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
• 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)