AI Article Synopsis
- Activated calcineurin in the heart causes cardiac hypertrophy, which can lead to serious heart conditions like failure and sudden death.
- Researchers used Drosophila (fruit flies) to study this by expressing active calcineurin, resulting in enlarged heart dimensions and lower contractility.
- They discovered that galactokinase acts as a modifier for calcineurin-induced cardiomyopathy, as its suppression reduced heart enlargement and other abnormalities caused by active calcineurin.
Article Abstract
Activated/uninhibited calcineurin is both necessary and sufficient to induce cardiac hypertrophy, a condition that often leads to dilated cardiomyopathy, heart failure, and sudden cardiac death. We expressed constitutively active calcineurin in the adult heart of Drosophila melanogaster and identified enlarged cardiac chamber dimensions and reduced cardiac contractility. In addition, expressing constitutively active calcineurin in the fly heart using the Gal4/UAS system induced an increase in heart wall thickness. We performed a targeted genetic screen for modifiers of calcineurin-induced cardiac enlargement based on previous calcineurin studies in the fly and identified galactokinase as a novel modifier of calcineurin-induced cardiomyopathy. Genomic deficiencies spanning the galactokinase locus, transposable elements that disrupt galactokinase, and cardiac-specific RNAi knockdown of galactokinase suppressed constitutively active calcineurin-induced cardiomyopathy. In addition, in flies expressing constitutively active calcineurin using the Gal4/UAS system, a transposable element in galactokinase suppressed the increase in heart wall thickness. Finally, genetic disruption of galactokinase suppressed calcineurin-induced wing vein abnormalities. Collectively, we generated a model for discovering novel modifiers of calcineurin-induced cardiac enlargement in the fly and identified galactokinase as a previously unknown regulator of calcineurin-induced cardiomyopathy in adult Drosophila.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196615 | PMC |
| http://dx.doi.org/10.1534/genetics.114.166777 | DOI Listing |
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Galactokinase is a novel modifier of calcineurin-induced cardiomyopathy in Drosophila.
Genetics
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Department of Cell Biology, Duke University, Durham, North Carolina 27710 Department of Medicine, Duke University, Durham, North Carolina 27710 Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina 27710
Article Synopsis
- Activated calcineurin in the heart causes cardiac hypertrophy, which can lead to serious heart conditions like failure and sudden death.
- Researchers used Drosophila (fruit flies) to study this by expressing active calcineurin, resulting in enlarged heart dimensions and lower contractility.
- They discovered that galactokinase acts as a modifier for calcineurin-induced cardiomyopathy, as its suppression reduced heart enlargement and other abnormalities caused by active calcineurin.
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October 2010
Department of Physiology, University of Toronto, Toronto, ON, Canada M5G 1A8.
Cardiac-specific overexpression of a constitutively active form of calcineurin A (CNA) leads directly to cardiac hypertrophy in the CNA mouse model. Because cardiac hypertrophy is a prominent characteristic of many cardiomyopathies, we deduced that delineating the proteomic profile of ventricular tissue from this model might identify novel, widely applicable therapeutic targets. Proteomic analysis was carried out by subjecting fractionated cardiac samples from CNA mice and their WT littermates to gel-free liquid chromatography linked to shotgun tandem mass spectrometry.
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Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC7020, Cincinnati Ohio 45229-3039, USA.
The calcium-calmodulin-activated protein phosphatase calcineurin functions as a key mediator of diverse biologic processes, including differentiation, apoptosis, growth, and adaptive responses, in part through dephosphorylation and activation of nuclear factor of activated T-cell (NFAT) transcription factors. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream component of the mitogen-activated protein kinases that serves as a pivotal regulator of cytokine-, oxidative-, and stress-induced cell death. Here, we performed a yeast two-hybrid screen with calcineurin B as bait, which identified ASK1 as a direct physical interacting partner.
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