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


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.
Moslehi
Javid
J
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, 44 Binney St, Boston, MA 02115, USA.
Minamishima
Yoji Andrew
YA
Shi
Jianru
J
Neuberg
Donna
D
Charytan
David M
DM
Padera
Robert F
RF
Signoretti
Sabina
S
Liao
Ronglih
R
Kaelin
William G
WG
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000503:physiopathology*; D015687:Cell Hypoxia / Q000502:physiology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism; D017682:Myocardial Stunning / Q000378:metabolism* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D011393:Procollagen-Proline Dioxygenase; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C522722:PHD3 protein, mouse; C490189:Egln1 protein, mouse