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Hypoxia-inducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2008 Jun; Vol. 28 (11), pp. 3790-803. Date of Electronic Publication: 2008 Feb 19. - Publication Year :
- 2008
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Abstract
- Hypoxia-inducible transcription factor 1 (HIF-1) and HIF-2alpha regulate the expression of an expansive array of genes associated with cellular responses to hypoxia. Although HIF-regulated genes mediate crucial beneficial short-term biological adaptations, we hypothesized that chronic activation of the HIF pathway in cardiac muscle, as occurs in advanced ischemic heart disease, is detrimental. We generated mice with cardiac myocyte-specific deletion of the von Hippel-Lindau protein (VHL), an essential component of an E3 ubiquitin ligase responsible for suppressing HIF levels during normoxia. These mice were born at expected frequency and thrived until after 3 months postbirth, when they developed severe progressive heart failure and premature death. VHL-null hearts developed lipid accumulation, myofibril rarefaction, altered nuclear morphology, myocyte loss, and fibrosis, features seen for various forms of human heart failure. Further, nearly 50% of VHL(-/-) hearts developed malignant cardiac tumors with features of rhabdomyosarcoma and the capacity to metastasize. As compelling evidence for the mechanistic contribution of HIF-1alpha, the concomitant deletion of VHL and HIF-1alpha in the heart prevented this phenotype and restored normal longevity. These findings strongly suggest that chronic activation of the HIF pathway in ischemic hearts is maladaptive and contributes to cardiac degeneration and progression to heart failure.
- Subjects :
- Animals
Capillaries growth & development
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic metabolism
Cell Transformation, Neoplastic pathology
ErbB Receptors metabolism
Gene Deletion
Gene Transfer Techniques
Heart Failure metabolism
Heart Neoplasms genetics
Heart Neoplasms metabolism
Heart Neoplasms pathology
Hypoxia metabolism
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Lipid Metabolism genetics
Lipids analysis
Mice
Mice, Knockout
Myocardium chemistry
Neovascularization, Physiologic genetics
Phosphorylation
Proto-Oncogene Proteins c-met metabolism
ras Proteins metabolism
Heart Failure genetics
Heart Failure pathology
Hypoxia genetics
Hypoxia pathology
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Myocardium metabolism
Myocardium pathology
Von Hippel-Lindau Tumor Suppressor Protein genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5549
- Volume :
- 28
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 18285456
- Full Text :
- https://doi.org/10.1128/MCB.01580-07