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

Moslehi J, Minamishima YA, Shi J, Neuberg D, Charytan DM, Padera RF, Signoretti S, Liao R, Kaelin WG
Circulation. 2010 122 (10): 1004-16

PMID: 20733101 · PMCID: PMC2971656 · DOI:10.1161/CIRCULATIONAHA.109.922427

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.

MeSH Terms (17)

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

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