Hypoxia-inducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein.

Lei, Li; Mason, Steve; Liu, Dinggang; Huang, Yan; Marks, Carolyn; Hickey, Reed; Jovin, Ion S; Pypaert, Marc; Johnson, Randall S; Giordano, Frank J

Lei, Li; Mason, Steve; Liu, Dinggang; Huang, Yan; Marks, Carolyn; Hickey, Reed; Jovin, Ion S; Pypaert, Marc; Johnson, Randall S; Giordano, Frank J.

Afiliación

Lei L; Cardiovascular Gene Therapy Program, Department of Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.

Mol Cell Biol ; 28(11): 3790-803, 2008 Jun.

Article en En | MEDLINE | ID: mdl-18285456

RESUMEN

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.

Asunto(s)

Insuficiencia Cardíaca/genética; Insuficiencia Cardíaca/patología; Subunidad alfa del Factor 1 Inducible por Hipoxia/genética; Hipoxia/genética; Hipoxia/patología; Miocardio/metabolismo; Miocardio/patología; Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética; Animales; Capilares/crecimiento & desarrollo; Transformación Celular Neoplásica/genética; Transformación Celular Neoplásica/metabolismo; Transformación Celular Neoplásica/patología; Receptores ErbB/metabolismo; Eliminación de Gen; Técnicas de Transferencia de Gen; Insuficiencia Cardíaca/metabolismo; Neoplasias Cardíacas/genética; Neoplasias Cardíacas/metabolismo; Neoplasias Cardíacas/patología; Hipoxia/metabolismo; Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo; Metabolismo de los Lípidos/genética; Lípidos/análisis; Ratones; Ratones Noqueados; Miocardio/química; Neovascularización Fisiológica/genética; Fosforilación; Proteínas Proto-Oncogénicas c-met/metabolismo; Proteínas ras/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau / Subunidad alfa del Factor 1 Inducible por Hipoxia / Insuficiencia Cardíaca / Hipoxia / Miocardio Límite: Animals Idioma: En Revista: Mol Cell Biol Año: 2008 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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