Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure
| Autor: | Javid Moslehi, Roderick T. Bronson, William G. Kaelin, Yoji Andrew Minamishima, Darragh Cullen, Nabeel Bardeesy |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Red Cells Immunology Procollagen-Proline Dioxygenase Volume overload Mice Transgenic Polycythemia Biochemistry Gene Expression Regulation Enzymologic Immediate early protein Hypoxia-Inducible Factor-Proline Dioxygenases Immediate-Early Proteins Hydroxylation Mice chemistry.chemical_compound Internal medicine medicine Animals Erythropoiesis RNA Messenger Alleles Cells Cultured Heart Failure biology Cell Biology Hematology medicine.disease DNA-Binding Proteins Enzyme Activation Mice Inbred C57BL Phenotype Endocrinology chemistry Echocardiography Erythropoietin Heart failure biology.protein Procollagen-proline dioxygenase EGLN1 medicine.drug |
| Zdroj: | Blood. 111:3236-3244 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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 HIFα 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. |
| Databáze: | OpenAIRE |
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