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Title: Muscle-specific regulation of right ventricular transcriptional responses to chronic hypoxia-induced hypertrophy by the muscle ring finger-1 (MuRF1) ubiquitin ligase in mice.

Authors: Oakley, Robert H; Campen, Matthew J; Paffett, Michael L; Chen, Xin; Wang, Zhongjing; Parry, Traci L; Hillhouse, Carolyn; Cidlowski, John A; Willis, Monte S

Published In BMC Med Genet, (2018 Sep 21)

Abstract: We recently identified a role for the muscle-specific ubiquitin ligase MuRF1 in right-sided heart failure secondary to pulmonary hypertension induced by chronic hypoxia (CH). MuRF1-/- mice exposed to CH are resistant to right ventricular (RV) dysfunction whereas MuRF1 Tg + mice exhibit impaired function indicative of heart failure. The present study was undertaken to understand the underlying transcriptional alterations in the RV of MuRF1-/- and MuRF1 Tg + mice.Microarray analysis was performed on RNA isolated from the RV of MuRF1-/-, MuRF1 Tg+, and wild-type control mice exposed to CH.MuRF1-/- RV differentially expressed 590 genes in response to CH. Analysis of the top 66 genes (> 2-fold or < - 2-fold) revealed significant associations with oxidoreductase, transcription regulation, and transmembrane component annotations. The significant genes had promoters enriched for HOXD12, HOXC13, and RREB-1 protein transcription factor binding sites. MuRF1 Tg + RV differentially expressed 150 genes in response to CH. Analysis of the top 45 genes (> 3-fold or < - 3-fold) revealed significant associations with oxidoreductase-metabolic, glycoprotein-transmembrane-integral proteins, and alternative splicing/splice variant annotations. The significant genes were enriched for promoters with ZIC1 protein transcription factor binding sites.The differentially expressed genes in MuRF1-/- and MuRF1 Tg + RV after CH have common functional annotations related to oxidoreductase (including antioxidant) and transmembrane component functions. Moreover, the functionally-enhanced MuRF1-/- hearts regulate genes related to transcription, homeobox proteins, and kinases/phosphorylation. These studies also reveal potential indirect effects of MuRF1 through regulating Rreb-1, and they reveal mechanisms by which MuRF1 may transcriptionally regulate anti-oxidant systems in the face of right heart failure.

PubMed ID: 30241514 Exiting the NIEHS site

MeSH Terms: Animals; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Gene Ontology; Heart Failure/genetics*; Heart Failure/metabolism; Heart Failure/physiopathology; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Humans; Hypoxia/genetics*; Hypoxia/metabolism; Hypoxia/physiopathology; Mice; Mice, Knockout; Microarray Analysis; Molecular Sequence Annotation; Muscle Proteins/deficiency; Muscle Proteins/genetics*; Promoter Regions, Genetic; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic*; Tripartite Motif Proteins/deficiency; Tripartite Motif Proteins/genetics*; Ubiquitin-Protein Ligases/deficiency; Ubiquitin-Protein Ligases/genetics*; Ventricular Dysfunction, Right/genetics*; Ventricular Dysfunction, Right/metabolism; Ventricular Dysfunction, Right/physiopathology

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