Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy

Javid Moslehi, Yoji Andrew Minamishima, Jianru Shi, Donna Neuberg, David M. Charytan, Robert F. Padera, Sabina Signoretti, Ronglih Liao, William G. Kaelin

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Background-: Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue, and how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The Prolyl Hydroxylase Domain-Containing Protein (PHD) prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability of the hypoxia-inducible factor transcription factor, a master regulator of genes that promote survival in a low-oxygen environment. Methods and results-: We found that cardiac-specific PHD inactivation causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, long-term expression of a stabilized hypoxia-inducible factor α variant in cardiomyocytes also led to dilated cardiomyopathy. Conclusion-: Sustained loss of PHD activity and subsequent hypoxia-inducible factor activation, as would occur in the setting of chronic ischemia, are sufficient to account for many of the changes in the hearts of individuals with chronic coronary artery disease.

Original languageEnglish
Pages (from-to)1004-1016
Number of pages13
JournalCirculation
Volume122
Issue number10
DOIs
Publication statusPublished - 2010 Sep 7

Keywords

  • cardiomyopathy
  • hibernation
  • hypoxia
  • ischemia
  • myocardium

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Moslehi, J., Minamishima, Y. A., Shi, J., Neuberg, D., Charytan, D. M., Padera, R. F., Signoretti, S., Liao, R., & Kaelin, W. G. (2010). Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. Circulation, 122(10), 1004-1016. https://doi.org/10.1161/CIRCULATIONAHA.109.922427