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Molecular and Cellular Biology, June 2008, p. 3790-3803, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.01580-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hypoxia-Inducible Factor-Dependent Degeneration, Failure, and Malignant Transformation of the Heart in the Absence of the von Hippel-Lindau Protein{triangledown}

Li Lei,1 Steve Mason,2 Dinggang Liu,1 Yan Huang,1 Carolyn Marks,3 Reed Hickey,1 Ion S. Jovin,1 Marc Pypaert,3 Randall S. Johnson,2 and Frank J. Giordano1*

Cardiovascular Gene Therapy Program, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510,1 Department of Biology, University of California San Diego, La Jolla, California,2 Electron Microscopy Core, Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 065103

Received 28 August 2007/ Returned for modification 1 October 2007/ Accepted 7 February 2008

Hypoxia-inducible transcription factor 1 (HIF-1) and HIF-2{alpha} 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-1{alpha}, the concomitant deletion of VHL and HIF-1{alpha} 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.

* Corresponding author. Mailing address: Cardiovascular Gene Therapy Program, Department of Medicine, Yale University School of Medicine, BCMM 436C, 295 Congress Avenue, New Haven, CT 06510. Phone: (203) 785-7631. Fax: (203) 737-2290. E-mail: frank.giordano{at}yale.edu

{triangledown} Published ahead of print on 19 February 2008.

Molecular and Cellular Biology, June 2008, p. 3790-3803, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.01580-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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