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| Status |
Public on Apr 01, 2016 |
| Title |
PHD2/3-dependent hydroxylation of thyroid hormone receptor-α mediates the transcriptional regulation of phospholamban to tune the cardiac response to chronic β-adrenergic stress |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Ischemic heart disease is the leading cause of heart failure. Both clinical trials and experimental animal studies demonstrate that chronic hypoxia can induce contractile dysfunction even before substantial ventricular damage, implicating a direct role of oxygen in the regulation of cardiac contractile function. Prolyl hydroxylase domain (PHD) proteins are well recognized as oxygen sensors and mediate a wide variety of cellular events by hydroxylating a growing list of protein substrates. Both PHD2 and 3 are highly expressed in the heart, yet their functional roles in modulating contractile function remain incompletely understood. Here, we report that combined deletion of PHD2 and 3 dramatically decreases the expression of phospholamban (PLN), results in sustained activation of CaMKII and sensitizes mice to myocardial injury induced by chronic β-adrenergic stress. We provide evidence that thyroid hormone receptor-α (TR-α), a transcriptional regulator of PLN, interacts with PHD2 and 3 and is hydroxylated at two proline residues. Inhibition of PHDs increases the interaction between TR-α and nuclear receptor co-repressor 2 (NCOR2) and suppresses PLN transcription. These observations provide new mechanistic insights into how oxygen directly modulates cardiac contractility, providing the possibility that cardiac function can be modulated therapeutically by tuning PHD enzymatic activity.
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| Overall design |
Two-condition experiment comparing gene expression in hearts isolated from PHD2/3f/f; Cre-/- and PHD2/3f/f; Cre+/- mice. Three biological replicates (mouse hearts) per condition.
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| Contributor(s) |
Schisler JC, Townley-Tilson WH, Xie L |
| Citation missing |
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| Submission date |
Apr 09, 2015 |
| Last update date |
Feb 02, 2018 |
| Contact name |
Jonathan C Schisler |
| E-mail(s) |
schisler@unc.edu
|
| Phone |
919-843-8708
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| Organization name |
The University of North Carolina at Chapel Hill
|
| Department |
McAllister Heart Institute
|
| Lab |
Schisler Lab
|
| Street address |
MBRB, Rm 2340C
|
| City |
Chapel Hill |
| State/province |
NC |
| ZIP/Postal code |
27599-7126 |
| Country |
USA |
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| Platforms (1) |
| GPL10787 |
Agilent-028005 SurePrint G3 Mouse GE 8x60K Microarray (Probe Name version) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA280758 |
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