title: Dynamic gene expression patterns in animal models of early and late heart failure reveal biphasic-bidirectional transcriptional activation of signaling pathways.
abstract: Altered cardiac gene expression in heart failure (HF) has mostly been identified by single-point analysis of end-stage disease. This may miss earlier changes in gene expression that are transient and/or directionally opposite to those observed later. Myocardial datasets from the largest microarray data repository (Gene Expression Omnibus) yielded six HF studies with time-course data. Differentially expressed transcripts between nonfailing controls, early HF (<3 days after cardiac insult) and late HF (usually >2 wk) were determined, and analysis of KEGG pathways and predicted regulatory control elements performed. We found that gene expression followed varying patterns: Downregulation of metabolic pathways occurred early and was sustained into late-stage HF. In contrast, most signaling pathways undergo a complex biphasic pattern: Calcium signaling, p53, apoptosis, and MAPK pathways displayed a bidirectional response, declining early but rising late. These profiles were compatible with specific microRNA (miRNA) and transcription regulators: Estrogen-related receptor-α and myocyte-enhancer factor-2 binding sites were overrepresented in the promoter regions of downregulated transcripts. Concurrently, there were overrepresented binding sites for E2f and ETS family members (E-Twenty Six, including Gabp, Elf1, and Ets2), serum response and interferon regulated factor in biphasic-bidirectional and late-upregulated transcripts. Binding sites for miRNAs downregulated by HF were more common in upregulated transcripts (e.g., miRNA-22,-133a/b, and -150 in early HF and miRNA-1,-9,-499 in late HF). During the development of HF, gene expression is characterized by dynamic overlapping sets of transcripts controlled by specific interrelated regulatory mechanisms. While metabolic gene classes show early and sustained downregulation in HF, signaling pathways undergo a complex biphasic pattern with early down- and more pronounced late upregulation.
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Janelle
authors.initials: J
authors.lastname: Rowell
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Norimichi
authors.initials: N
authors.lastname: Koitabashi
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland abarth3@jhmi.edu.
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Barth
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008810:Mice, Inbred C57BL; D008955:Models, Cardiovascular; D015398:Signal Transduction / Q000235:genetics*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D014157:Transcription Factors
keywords: gene expression; genomics; heart failure; meta-analysis; signaling pathways