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

Javid Moslehi, Yoji Andrew Minamishima, Jianru Shi, Donna Neuberg, David M. Charytan, Robert F. Padera, Sabina Signoretti, Ronglih Liao, William G. Kaelin

Research output: Contribution to journalArticle

72 Citations (Scopus)

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 α variant in cardiomyocytes also led to dilated cardiomyopathy. Conclusion-: 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.

Original languageEnglish
Pages (from-to)1004-1016
Number of pages13
JournalCirculation
Volume122
Issue number10
DOIs
Publication statusPublished - 2010 Sep 7

Fingerprint

Prolyl Hydroxylases
Cardiomyopathies
Cardiac Myocytes
Oxygen
Dilated Cardiomyopathy
Left Ventricular Dysfunction
Regulator Genes
Coronary Artery Disease
Transcription Factors
Ischemia
Heart Failure
Morbidity
Food
Mortality
Hypoxia
Enzymes
Protein Domains

Keywords

  • cardiomyopathy
  • hibernation
  • hypoxia
  • ischemia
  • myocardium

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Moslehi, J., Minamishima, Y. A., Shi, J., Neuberg, D., Charytan, D. M., Padera, R. F., ... Kaelin, W. G. (2010). Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. Circulation, 122(10), 1004-1016. https://doi.org/10.1161/CIRCULATIONAHA.109.922427

Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. / Moslehi, Javid; Minamishima, Yoji Andrew; Shi, Jianru; Neuberg, Donna; Charytan, David M.; Padera, Robert F.; Signoretti, Sabina; Liao, Ronglih; Kaelin, William G.

In: Circulation, Vol. 122, No. 10, 07.09.2010, p. 1004-1016.

Research output: Contribution to journalArticle

Moslehi, J, Minamishima, YA, Shi, J, Neuberg, D, Charytan, DM, Padera, RF, Signoretti, S, Liao, R & Kaelin, WG 2010, 'Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy', Circulation, vol. 122, no. 10, pp. 1004-1016. https://doi.org/10.1161/CIRCULATIONAHA.109.922427
Moslehi, Javid ; Minamishima, Yoji Andrew ; Shi, Jianru ; Neuberg, Donna ; Charytan, David M. ; Padera, Robert F. ; Signoretti, Sabina ; Liao, Ronglih ; Kaelin, William G. / Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. In: Circulation. 2010 ; Vol. 122, No. 10. pp. 1004-1016.
@article{b3eb4d18d4b340cb87607c8ad40ac9dc,
title = "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 α variant in cardiomyocytes also led to dilated cardiomyopathy. Conclusion-: 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.",
keywords = "cardiomyopathy, hibernation, hypoxia, ischemia, myocardium",
author = "Javid Moslehi and Minamishima, {Yoji Andrew} and Jianru Shi and Donna Neuberg and Charytan, {David M.} and Padera, {Robert F.} and Sabina Signoretti and Ronglih Liao and Kaelin, {William G.}",
year = "2010",
month = "9",
day = "7",
doi = "10.1161/CIRCULATIONAHA.109.922427",
language = "English",
volume = "122",
pages = "1004--1016",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy

AU - Moslehi, Javid

AU - Minamishima, Yoji Andrew

AU - Shi, Jianru

AU - Neuberg, Donna

AU - Charytan, David M.

AU - Padera, Robert F.

AU - Signoretti, Sabina

AU - Liao, Ronglih

AU - Kaelin, William G.

PY - 2010/9/7

Y1 - 2010/9/7

N2 - 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 α variant in cardiomyocytes also led to dilated cardiomyopathy. Conclusion-: 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.

AB - 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 α variant in cardiomyocytes also led to dilated cardiomyopathy. Conclusion-: 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.

KW - cardiomyopathy

KW - hibernation

KW - hypoxia

KW - ischemia

KW - myocardium

UR - http://www.scopus.com/inward/record.url?scp=77957254118&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957254118&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.109.922427

DO - 10.1161/CIRCULATIONAHA.109.922427

M3 - Article

VL - 122

SP - 1004

EP - 1016

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 10

ER -