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

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 alpha variant in cardiomyocytes also led to dilated cardiomyopathy.

CONCLUSIONS:

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.

• Authors: Javid Moslehi, Yoji Andrew Minamishima, Jianru Shi, Donna Neuberg, David M Charytan, Robert F Padera, Sabina Signoretti, Ronglih Liao, William G Kaelin Jr
• Journal: Circulation (Circulation) Vol. 122 Issue 10 Pg. 1004-16 (Sep 07 2010) ISSN: 1524-4539 [Electronic] United States
• PMID: 20733101 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• endothelial PAS domain-containing protein 1
• PHD3 protein, mouse
• Procollagen-Proline Dioxygenase
• Egln1 protein, mouse
• Hypoxia-Inducible Factor-Proline Dioxygenases

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Cardiomyopathy, Dilated (metabolism, physiopathology)
• Cell Hypoxia (physiology)
• Heart Failure (metabolism, physiopathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Hypoxia-Inducible Factor-Proline Dioxygenases
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Mitochondria (metabolism)
• Myocardial Stunning (metabolism, physiopathology)
• Myocardium (metabolism)
• Myocytes, Cardiac (cytology, enzymology)
• Neovascularization, Physiologic (physiology)
• Phenotype
• Procollagen-Proline Dioxygenase (genetics, metabolism)