Loss of Hypoxia-Inducible Factor Prolyl Hydroxylase Activity in Cardiomyocytes Phenocopies Ischemic Cardiomyopathy

• Published in: Circulation (New York, N.Y.) N.Y.), 2010-09, Vol.122 (10), p.1004-1016
• Main Authors: MOSLEHI, Javid, MINAMISHIMA, Yoji Andrew, JIANRU SHI, NEUBERG, Donna, CHARYTAN, David M, PADERA, Robert F, SIGNORETTI, Sabina, LIAO, Ronglih, KAELIN, William G
• Format: Article
• Language: English
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiomyopathy, Dilated - metabolism; Cardiomyopathy, Dilated - physiopathology; Cell Hypoxia - physiology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fundamental and applied biological sciences. Psychology; General aspects; Heart Failure - metabolism; Heart Failure - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-Inducible Factor-Proline Dioxygenases; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mitochondria - metabolism; Myocardial Stunning - metabolism; Myocardial Stunning - physiopathology; Myocardium - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - enzymology; Neovascularization, Physiologic - physiology; Phenotype; Procollagen-Proline Dioxygenase - genetics; Procollagen-Proline Dioxygenase - metabolism; Vertebrates: cardiovascular system
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.109.922427

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. 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. 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.