Document Detail


Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy.
MedLine Citation:
PMID:  20733101     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-08-23
Journal Detail:
Title:  Circulation     Volume:  122     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-08     Completed Date:  2010-09-29     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1004-16     Citation Subset:  AIM; IM    
Affiliation:
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, 44 Binney St, Boston, MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
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
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
Grant Support
ID/Acronym/Agency:
K08HL097031/HL/NHLBI NIH HHS; R01 CA068490-15/CA/NCI NIH HHS; T32HL007604-24/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Hif1a protein, mouse; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/endothelial PAS domain-containing protein 1; EC 1.14.11.2/Egln1 protein, mouse; EC 1.14.11.2/PHD3 protein, mouse; EC 1.14.11.2/Procollagen-Proline Dioxygenase
Comments/Corrections

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