title: Combined deep microRNA and mRNA sequencing identifies protective transcriptomal signature of enhanced PI3Kα signaling in cardiac hypertrophy.
abstract: 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.
authors.affiliation: Department of Developmental Biology, Washington University Medical School, St Louis, MO 63110-1093, USA.
authors.forename: Kai-Chien
authors.initials: KC
authors.lastname: Yang
authors.forename: Yuan-Chieh
authors.initials: YC
authors.lastname: Ku
authors.forename: Michael
authors.initials: M
authors.lastname: Lovett
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Nerbonne
mesh_terms: D000818:Animals; D001483:Base Sequence; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D016000:Cluster Analysis; D004719:Endomyocardial Fibrosis / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006352:Heart Ventricles / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D012333:RNA, Messenger / Q000737:chemistry* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D059467:Transcriptome; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D058543:Class Ia Phosphatidylinositol 3-Kinase