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Impaired cardiac hypertrophic response in Calcineurin Abeta -deficient mice
Orlando F Bueno1, Benjamin J Wilkins, Kevin M Tymitz
1Divisions of Molecular Cardiovascular Biology and Cardiology, Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Abstract:
Calcineurin is a calcium-calmodulin-regulated, serine-threonine phosphatase that functions as a key inducer of stress responsive gene expression in multiple cell types through a direct activation of nuclear factor of activated T cells and myocyte enhancer factor 2 transcription factors. In cardiomyocytes, calcineurin signaling has been implicated in the regulation of the hypertrophic response caused by pressure overload or neuroendocrine stimulation. Three separate genes encode the catalytic subunit of calcineurin in mammalian cells, CnAalpha, CnAbeta, and CnAgamma. To evaluate the necessary function of calcineurin as a hypertrophic regulatory factor, the CnAbeta gene was disrupted in the mouse. CnAbeta-deficient mice were viable, fertile, and overtly normal well into adulthood, but displayed a 80% decrease in calcineurin enzymatic activity in the heart that was associated with a 12% reduction in basal heart size. CnAbeta-deficient mice were dramatically impaired in their ability to mount a productive hypertrophic response induced by pressure overload, angiotensin II infusion, or isoproterenol infusion. Analysis of marker genes associated with the hypertrophic response revealed a partial defect in the molecular program of hypertrophy. Collectively, these data solidify the hypothesis that calcineurin functions as a central regulator of the cardiac hypertrophic growth response in vivo.
Insights
Calcineurin signaling, specifically the CnAbeta gene, is crucial for cardiac hypertrophy in mice. Disabling this gene significantly impairs the heart's ability to grow in response to stress.
Area of Science:
- Cardiovascular Biology
- Molecular Cell Biology
- Physiology
Background:
- Calcineurin is a calcium-calmodulin-regulated phosphatase.
- It activates transcription factors, inducing stress-responsive genes.
- In cardiomyocytes, calcineurin signaling regulates hypertrophic responses.
Purpose of the Study:
- To investigate the essential role of calcineurin in cardiac hypertrophy.
- To evaluate the function of the CnAbeta gene in this process.
Main Methods:
- Gene disruption of CnAbeta in mice.
- Measurement of calcineurin enzymatic activity in the heart.
- Assessment of cardiac hypertrophy in response to various stimuli (pressure overload, angiotensin II, isoproterenol).
- Analysis of hypertrophic marker genes.
Main Results:
- CnAbeta-deficient mice showed an 80% reduction in heart calcineurin activity.
- These mice had a 12% smaller basal heart size.
- CnAbeta-deficient mice were significantly impaired in hypertrophic responses to stimuli.
- A partial defect in the molecular program of hypertrophy was observed.
Conclusions:
- Calcineurin, particularly the CnAbeta subunit, is a central regulator of cardiac hypertrophic growth in vivo.
- These findings solidify the hypothesis of calcineurin's critical role in cardiac adaptation to stress.