Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
PHD2/3-dependent hydroxylation tunes cardiac response to β-adrenergic stress via phospholamban
Liang Xie, … , Gerhard Meissner, Cam Patterson
Liang Xie, … , Gerhard Meissner, Cam Patterson
Published June 15, 2015
Citation Information: J Clin Invest. 2015;125(7):2759-2771. https://doi.org/10.1172/JCI80369.
View: Text | PDF
Research Article Cardiology Article has an altmetric score of 3

PHD2/3-dependent hydroxylation tunes cardiac response to β-adrenergic stress via phospholamban

  • Text
  • PDF
Abstract

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 PHD3 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 Phd3 dramatically decreased expression of phospholamban (PLN), resulted in sustained activation of calcium/calmodulin-activated kinase II (CaMKII), and sensitized mice to chronic β-adrenergic stress–induced myocardial injury. We have provided evidence that thyroid hormone receptor-α (TR-α), a transcriptional regulator of PLN, interacts with PHD2 and PHD3 and is hydroxylated at 2 proline residues. Inhibition of PHDs increased the interaction between TR-α and nuclear receptor corepressor 2 (NCOR2) and suppressed Pln transcription. Together, these observations provide mechanistic insight into how oxygen directly modulates cardiac contractility and suggest that cardiac function could be modulated therapeutically by tuning PHD enzymatic activity.

Authors

Liang Xie, Xinchun Pi, W.H. Davin Townley-Tilson, Na Li, Xander H.T. Wehrens, Mark L. Entman, George E. Taffet, Ashutosh Mishra, Junmin Peng, Jonathan C. Schisler, Gerhard Meissner, Cam Patterson

×

Figure 6

Hypoxia decreases PLN protein levels and suppresses Pln transcription.

Options: View larger image (or click on image) Download as PowerPoint
Hypoxia decreases PLN protein levels and suppresses Pln transcription.
N...
Neonatal rat ventricular myocytes were treated with hypoxia (1% O2) as indicated. Cells were then harvested for protein or mRNA analysis. (A and B) Western blot analyses were performed with the indicated antibodies (A). Densitometric analysis from 3 experiments is shown in B. *P < 0.05; **P < 0.01, compared with 0 hours, 1-way ANOVA. (C) Real-time PCR was performed to analyze relative Pln mRNA levels. n = 3, *P < 0.05; **P < 0.01, compared with 0 hours, 1-way ANOVA. (D) HL-1 cardiomyocytes were transfected with a pGL3-Pln promoter (–156 to +64) luciferase construct, together with pcDNA3, or with a construct expressing TR-α or NCOR2, as indicated. Cells were also cotransfected with a construct expressing Renilla luciferase as the internal control. Twenty-four hours after transfection, cells were cultured under 21% or 1% O2 conditions for 24 hours. Cells were then harvested and luciferase activity determined with a luminometer. Relative luciferase activity was calculated from 3 separate experiments. *P < 0.05; #P < 0.01, 2-way ANOVA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 4 X users
On 1 Facebook pages
66 readers on Mendeley
See more details