title: Systems analysis reveals down-regulation of a network of pro-survival miRNAs drives the apoptotic response in dilated cardiomyopathy.
abstract: Apoptosis is a hallmark of multiple etiologies of heart failure, including dilated cardiomyopathy. Since microRNAs are master regulators of cardiac development and key effectors of intracellular signaling, they represent novel candidates for understanding the mechanisms driving the increased dysfunction and loss of cardiomyocytes during cardiovascular disease progression. To determine the role of cardiac miRNAs in the apoptotic response, we used microarray technology to monitor miRNA levels in a validated murine phospholambam mutant model of dilated cardiomyopathy. 24 miRNAs were found to be differentially expressed, most of which have not been previously linked to dilated cardiomyopathy. We showed that individual silencing of 7 out of 8 significantly down-regulated miRNAs (mir-1, -29c, -30c, -30d, -149, -486, -499) led to a strong apoptotic phenotype in cell culture, suggesting they repress pro-apoptotic factors. To identify putative miRNA targets most likely relevant to cell death, we computationally integrated transcriptomic, proteomic and functional annotation data. We showed the dependency of prioritized target abundance on miRNA expression using RNA interference and quantitative mass spectrometry. We concluded that down regulation of key pro-survival miRNAs causes up-regulation of apoptotic signaling effectors that contribute to cardiac cell loss, potentially leading to system decompensation and heart failure.
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario, Canada M5S 3E1. andrew.emili@utoronto.ca.
authors.forename: Ruth
authors.initials: R
authors.lastname: Isserlin
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.forename: Dingyan
authors.initials: D
authors.lastname: Wang
authors.forename: Dajana
authors.initials: D
authors.lastname: Vuckovic
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bousette
authors.forename: Anthony O
authors.initials: AO
authors.lastname: Gramolini
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.forename: Andrew
authors.initials: A
authors.lastname: Emili
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D016000:Cluster Analysis; D019295:Computational Biology; D004195:Disease Models, Animal; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D015203:Reproducibility of Results
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger