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

Abstract

Hypoxia-inducible transcription factor 1 (HIF-1) and HIF-2␣ 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␣, the concomitant deletion of VHL and HIF-1␣ 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.In the cardiovascular system, hypoxia is encountered in a number of important clinical settings, including sleep apnea, chronic obstructive pulmonary disease, and, most commonly, ischemic heart disease (IHD). Myocardial hypoxia, as a component of ischemia, may also occur in other common clinical conditions, such as valve disease, pathological cardiac hypertrophy, and severe systemic hypertension. As such, understanding how hypoxia-induced molecular changes affect the heart is of great importance. Altered gene expression mediated by hypoxia-inducible transcription factor 1␣ (HIF-1␣) and HIF-2␣ is one of the most fundamental and ubiquitous mechanisms whereby biological adaptations to hypoxia occur. The HIFs are basic helix-loop-helix transcription factors that regulate the expression of a wide repertoire of genes involved in a myriad of biological functions, including angiogenesis, apoptosis, and cellular metabolism (14,17,51). A third family member, HIF-3␣, lacks a transcriptional activation domain and may act as a competitive inhibitor of HIF-1␣ and -2␣ activity (41).Although HIF-1␣ and -2␣ appear to bind the same hypoxia response elements (HREs) in hypoxia-inducible genes, it has been established that they preferentially regulate different genes in different cell types and therefore are not redundant.The role of HIF-1␣ in the transcriptional control of angiogenesis has led to the ongoing development of HIF-1␣ as a therapeutic stimulator of angiogenesis in IHD and peripheral vascular disease (12,15,48,60), although clinical development of HIF-2␣ for this purpose has also been considered. Others and we ...

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