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

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 oxygen-dependent posttranslational modification (prolyl hydroxylation) marks the HIFalpha 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.
Authors	Yoji Andrew Minamishima, Javid Moslehi, Nabeel Bardeesy, Darragh Cullen, Roderick T Bronson, William G Kaelin Jr
Journal	Blood (Blood) Vol. 111 Issue 6 Pg. 3236-44 (Mar 15 2008) ISSN: 0006-4971 [Print] United States
PMID	18096761 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	DNA-Binding Proteins Immediate-Early Proteins RNA, Messenger Procollagen-Proline Dioxygenase Egln1 protein, mouse Hypoxia-Inducible Factor-Proline Dioxygenases
Topics	Alleles Animals Cells, Cultured DNA-Binding Proteins (genetics, metabolism) Echocardiography Enzyme Activation Erythropoiesis (genetics) Gene Expression Regulation, Enzymologic Heart Failure (diagnostic imaging, enzymology, genetics) Hypoxia-Inducible Factor-Proline Dioxygenases Immediate-Early Proteins (genetics, metabolism) Mice Mice, Inbred C57BL Mice, Transgenic Phenotype Polycythemia (enzymology, genetics, pathology) Procollagen-Proline Dioxygenase RNA, Messenger (genetics)

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