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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number175
JournalBMC Medical Genetics
Volume19
Issue number1
DOIs
StatePublished - Sep 21 2018

Fingerprint

Ligases
Ubiquitin
Hypertrophy
Fingers
Muscles
Heart Failure
Genes
Hypoxia
Oxidoreductases
Protein Splicing
Right Ventricular Dysfunction
Homeodomain Proteins
Alternative Splicing
Microarray Analysis
Pulmonary Hypertension
Oxidants
Protein Kinases
Glycoproteins
Transcription Factors
Antioxidants

Keywords

  • Gene expression
  • Hypoxia
  • Microarray
  • MuRF1
  • Right heart failure

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Muscle-specific regulation of right ventricular transcriptional responses to chronic hypoxia-induced hypertrophy by the muscle ring finger-1 (MuRF1) ubiquitin ligase in mice. / Oakley, Robert H.; Campen, Matthew J.; Paffett, Michael L.; Chen, Xin; Wang, Zhongjing; Parry, Traci L.; Hillhouse, Carolyn; Cidlowski, John A.; Willis, Monte.

In: BMC Medical Genetics, Vol. 19, No. 1, 175, 21.09.2018.

Research output: Contribution to journalArticle

Oakley, Robert H. ; Campen, Matthew J. ; Paffett, Michael L. ; Chen, Xin ; Wang, Zhongjing ; Parry, Traci L. ; Hillhouse, Carolyn ; Cidlowski, John A. ; Willis, Monte. / Muscle-specific regulation of right ventricular transcriptional responses to chronic hypoxia-induced hypertrophy by the muscle ring finger-1 (MuRF1) ubiquitin ligase in mice. In: BMC Medical Genetics. 2018 ; Vol. 19, No. 1.
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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.",
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AU - Oakley, Robert H.

AU - Campen, Matthew J.

AU - Paffett, Michael L.

AU - Chen, Xin

AU - Wang, Zhongjing

AU - Parry, Traci L.

AU - Hillhouse, Carolyn

AU - Cidlowski, John A.

AU - Willis, Monte

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N2 - 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.

AB - 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.

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KW - Hypoxia

KW - Microarray

KW - MuRF1

KW - Right heart failure

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