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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3236-3244.
Prepublished online as a Blood First Edition Paper on December 20, 2007; DOI 10.1182/blood-2007-10-117812.
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Submitted October 25, 2007
Accepted December 18, 2007
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, and William G Kaelin Jr.*
Department of Medical Oncology, Brigham and Women's Hopsital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, United States
Department of Pathology, Rodent Histopathology Core, Harvard Medical School, Boston, MA, United States
Howard Hughes Medical Institute, Chevy Chase, MD, United States
* Corresponding author; email: william_kaelin{at}dfci.harvard.edu.
Pharmacological 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 oxygen-dependent posttranslational modification (prolyl hydroxylation) marks the HIF subunit for polyubiquitination and destruction. Three enzymes (PHD1, PHD2, and PHD3) capable of catalyzing this reaction have been identified although PHD2 (also called EGLN1) 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.
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