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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.
- Abstract
Background: 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. Methods: Microarray analysis was performed on RNA isolated from the RV of MuRF1−/−, MuRF1 Tg+, and wild-type control mice exposed to CH. Results: 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. Conclusions: 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.
- Subjects
TRANSCRIPTION factors; HYPOXEMIA; HYPERTROPHY; UBIQUITIN ligases; PHOSPHORYLATION
- Publication
BMC Medical Genetics, 2018, Vol 19, Issue 1, pN.PAG
- ISSN
1471-2350
- Publication type
Article
- DOI
10.1186/s12881-018-0670-1