Aiming straight for the heart: Prolyl hydroxylases set the BAR

The cellular response to a reduced oxygen state (or hypoxia) includes de novo alterations in gene expression patterns, many of which are controlled by hypoxiainducible factor (HIF) transcription factors. HIF signaling is predominantly regulated by the dioxygenase family of prolyl hydroxylases (PHDs), also known as EGL nine homologs (EGLNs). The PHD family in higher eukaryotes, like the HIF α family, is composed of multiple members that have some shared biochemical properties yet have unique biological roles. Although HIF members are the major substrates identified to date for the PHD members, a reasonable expectation is that other proteins whose activities are altered by hypoxia may also serve as PHD substrates. Indeed, the β₂- adrenergic receptor, a major adrenergic heterotrimeric guanine nucleotide- binding protein-coupled receptor in the heart, has been identified as a substrate for PHD3.