Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure

Yoji Andrew Minamishima, Javid Moslehi, Nabeel Bardeesy, Darragh Cullen, Roderick T. Bronson, William G. Kaelin

Research output: Contribution to journalArticle

189 Citations (Scopus)

Abstract

Pharmacologic activation of the heterodimeric HIF transcription factor appears promising as a strategy to treat diseases, such as anemia, myocardial infarction, and stroke, in which tissue hypoxia is a prominent feature. HIF accumulation is normally linked to oxygen availability because an oxygendependent posttranslational modification (prolyl hydroxylation) marks the HIFα subunit for polyubiquitination and destruction. Three enzymes (PHD1, PHD2, and PHD3) capable of catalyzing this reaction have been identified, although PHD2 (also called Eglnl) appears to be the primary HIF prolyl hydroxylase in cell culture experiments. We found that conditional inactivation of PHD2 in mice is sufficient to activate a subset of HIF target genes, including erythropoietin, leading to striking increases in red blood cell production. Mice lacking PHD2 exhibit premature mortality associated with marked venous congestion and dilated cardiomyopathy. The latter is likely the result of hyperviscosity syndrome and volume overload, although a direct effect of chronic, high-level HIF stimulation on cardiac myocytes cannot be excluded.

Original languageEnglish
Pages (from-to)3236-3244
Number of pages9
JournalBlood
Volume111
Issue number6
DOIs
Publication statusPublished - 2008 Mar 15

Fingerprint

Prolyl Hydroxylases
Polycythemia
Hydroxylation
Erythropoietin
Cell culture
Blood
Transcription Factors
Heart Failure
Genes
Chemical activation
Cells
Availability
Tissue
Oxygen
Premature Mortality
Hyperemia
Dilated Cardiomyopathy
Enzymes
Post Translational Protein Processing
Cardiac Myocytes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Minamishima, Y. A., Moslehi, J., Bardeesy, N., Cullen, D., Bronson, R. T., & Kaelin, W. G. (2008). Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood, 111(6), 3236-3244. https://doi.org/10.1182/blood-2007-10-117812

Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. / Minamishima, Yoji Andrew; Moslehi, Javid; Bardeesy, Nabeel; Cullen, Darragh; Bronson, Roderick T.; Kaelin, William G.

In: Blood, Vol. 111, No. 6, 15.03.2008, p. 3236-3244.

Research output: Contribution to journalArticle

Minamishima, YA, Moslehi, J, Bardeesy, N, Cullen, D, Bronson, RT & Kaelin, WG 2008, 'Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure', Blood, vol. 111, no. 6, pp. 3236-3244. https://doi.org/10.1182/blood-2007-10-117812
Minamishima YA, Moslehi J, Bardeesy N, Cullen D, Bronson RT, Kaelin WG. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood. 2008 Mar 15;111(6):3236-3244. https://doi.org/10.1182/blood-2007-10-117812
Minamishima, Yoji Andrew ; Moslehi, Javid ; Bardeesy, Nabeel ; Cullen, Darragh ; Bronson, Roderick T. ; Kaelin, William G. / Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. In: Blood. 2008 ; Vol. 111, No. 6. pp. 3236-3244.
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