Document Detail

Combined deep microRNA and mRNA sequencing identifies protective transcriptomal signature of enhanced PI3Kα signaling in cardiac hypertrophy.
MedLine Citation:
PMID:  22580345     Owner:  NLM     Status:  MEDLINE    
The perturbation of myocardial transcriptome homeostasis is the hallmark of pathological hypertrophy, underlying the maladaptive myocardial remodeling secondary to pathological stresses. Classic and novel therapeutics that provide beneficial effects against pathological remodeling likely impact myocardial transcriptome architecture, including miRNA and mRNA expression profiles. Microarray and PCR-based technologies, although employed extensively, cannot provide adequate sequence coverage or quantitative accuracy to test this hypothesis directly. The goal of this study was to develop and exploit next-generation sequencing approaches for comprehensive and quantitative analyses of myocardial miRNAs and mRNAs to test the hypothesis that augmented phosphoinositide-3-kinase-p110α (PI3Kα) signaling in the setting of pathological hypertrophy provides beneficial effects through remodeling of the myocardial transcriptome signature. In these studies, a molecular and bioinformatic pipeline permitting comprehensive analysis and quantification of myocardial miRNA and mRNA expression with next-generation sequencing was developed and the impact of enhanced PI3Kα signaling on the myocardial transcriptome signature of pressure overload-induced pathological hypertrophy was explored. These analyses identified multiple miRNAs and mRNAs that were abnormally expressed in pathological hypertrophy and partially or completely normalized with increased PI3Kα signaling. Additionally, several novel miRNAs potentially linked to remodeling in cardiac hypertrophy were identified. Additional experiments revealed that increased PI3Kα signaling reduces cardiac fibrosis in pathological hypertrophy through modulating TGF-β signaling and miR-21 expression. In conclusion, using the approach of combined miRNA and mRNA sequencing, we identify the protective transcriptome signature of enhanced PI3Kα signaling in the context of pathological hypertrophy, and demonstrate the regulation of TGF-β/miR-21 by which enhanced PI3Kα signaling protects against cardiac fibrosis.
Kai-Chien Yang; Yuan-Chieh Ku; Michael Lovett; Jeanne M Nerbonne
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-11
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  53     ISSN:  1095-8584     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-11     Completed Date:  2012-10-19     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  101-12     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Department of Developmental Biology, Washington University Medical School, St Louis, MO 63110-1093, USA.
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MeSH Terms
Base Sequence
Cardiomegaly / enzymology,  genetics*,  metabolism
Class Ia Phosphatidylinositol 3-Kinase / metabolism*
Cluster Analysis
Endomyocardial Fibrosis / genetics,  metabolism
Gene Expression Profiling
Heart Ventricles / metabolism
High-Throughput Nucleotide Sequencing*
Mice, Transgenic
MicroRNAs / chemistry*,  metabolism
Molecular Sequence Data
Nucleic Acid Conformation
RNA, Messenger / chemistry*,  metabolism
Sequence Analysis, RNA*
Signal Transduction
Ventricular Remodeling / genetics
Grant Support
Reg. No./Substance:
0/MIRN21 microRNA, mouse; 0/MicroRNAs; 0/RNA, Messenger; EC Ia Phosphatidylinositol 3-Kinase

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