Novel Drugs and the Response to Hypoxia: HIF Stabilizers and Prolyl Hydroxylase

Tissue hypoxia occurs when local metabolism is disturbed by an imbalance between oxygen supply and consumption. This condition can lead to a variety of serious ischemic disorders, including a number of important cardiovascular diseases. In the search for therapeutic approaches, focused modalities which specifically target hypoxia have been particularly sought. These efforts would profit from the ability to utilize the mechanisms by which cells adjust to hypoxic conditions. At the center of the cellular response to hypoxia is hypoxia-inducible factor, HIF. This factor is composed of two subunits, an oxygen-sensitive HIF-α subunit and a constitutively expressed HIF-β subunit. Intracellular accumulation of HIF induces the coordinated expression of a number of adaptive genes against hypoxic insult. Because activation of HIF is a promising therapeutic modality for ischemic cardiovascular disease, recent studies have focused on the development of HIF stimulators. HIF levels are regulated by prolyl hydroxylation and asparaginyl hydroxylation of the HIF-α subunit. To date, a single HIF asparaginyl hydroxylase has been identified, factor inhibiting HIF (FIH), whereas the mammalian genome encodes three closely related proteins that have HIF prolyl hydroxylase activity, PHD1, PHD2 and PHD3. Recent patents have disclosed methods for identifying modulators of HIF or PHD as well as novel compounds with properties of HIF modulation or prolyl hydroxylase inhibition. This review highlights the identification of novel HIF stabilizers as specific molecularly targeted therapies against cardiovascular disease.