| Constitutively active calcineurin induces cardiac endoplasmic reticulum stress and protects against apoptosis that is mediated by alpha-crystallin-B. | |
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MedLine Citation:
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PMID: 20937869 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. We identified 1,918 proteins with high confidence, of which 290 were differentially expressed. Microarray analysis of the same tissue provided us with alterations in the ventricular transcriptome. Because bioinformatic analyses of both the proteome and transcriptome demonstrated the up-regulation of endoplasmic reticulum stress, we validated its occurrence in adult CNA hearts through a series of immunoblots and RT-PCR analyses. Endoplasmic reticulum stress often leads to increased apoptosis, but apoptosis was minimal in CNA hearts, suggesting that activated calcineurin might protect against apoptosis. Indeed, the viability of cultured neonatal mouse cardiomyocytes (NCMs) from CNA mice was higher than WT after serum starvation, an apoptotic trigger. Proteomic data identified α-crystallin B (Cryab) as a potential mediator of this protective effect and we showed that silencing of Cryab via lentivector-mediated transduction of shRNAs in NCMs led to a significant reduction in NCM viability and loss of protection against apoptosis. The identification of Cryab as a downstream effector of calcineurin-induced protection against apoptosis will permit elucidation of its role in cardiac apoptosis and its potential as a therapeutic target. |
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Authors:
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Nicolas Bousette; Shaan Chugh; Vincent Fong; Ruth Isserlin; Kyoung-Han Kim; Allen Volchuk; Peter H Backx; Peter Liu; Thomas Kislinger; David H MacLennan; Andrew Emili; Anthony O Gramolini |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-11 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 107 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-27 Completed Date: 2010-11-22 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 18481-6 Citation Subset: IM |
Affiliation:
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Department of Physiology, University of Toronto, Toronto, ON, Canada M5G 1A8. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / physiology Calcineurin / genetics, metabolism* Cardiomegaly / genetics, metabolism, pathology Endoplasmic Reticulum / metabolism* Gene Expression Gene Expression Profiling Gene Knockdown Techniques Mice Mice, Transgenic Myocardium / cytology, metabolism* Protein Array Analysis Proteomics RNA, Small Interfering / genetics Stress, Physiological alpha-Crystallin B Chain / antagonists & inhibitors, genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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MT 125450//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/RNA, Small Interfering; 0/alpha-Crystallin B Chain; EC 3.1.3.16/Calcineurin |
| Comments/Corrections | |
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