Hypoxia-inducible factor as a therapeutic target for cardioprotection.
Hypoxia inducible factor (HIF) is an oxygen-sensitive transcription factor that enables aerobic organisms to adapt to hypoxia. This is achieved through the transcriptional activation of up to 200 genes, many of which are critical to cell survival. Under conditions of normoxia, the hydroxylation of HIF by prolyl hydroxylase domain-containing (PHD) enzymes targets it for polyubiquitination and proteosomal degradation by the von Hippel-Lindau protein (VHL). However, under hypoxic conditions, PHD activity is inhibited, thereby allowing HIF to accumulate and translocate to the nucleus, where it binds to the hypoxia-responsive element sequences of target gene promoters. Experimental studies suggest that HIF may act as a mediator of ischemic preconditioning, and that the genetic or pharmacological stabilization of HIF under normoxic conditions, may protect the heart against the detrimental effects of acute ischemia-reperfusion injury. The mechanisms underlying the cardioprotective effect of HIF are unclear, but it may be attributed to the transcriptional activation of genes associated with cardioprotection such as erythropoietin, heme oxygenase-1, and inducible nitric oxide synthase or it may be due to reprogramming of cell metabolism. In this review article, we highlight the role of HIF in mediating both adaptive and pathological processes in the heart, as well as focusing on the therapeutic potential of the HIF-signaling pathway as a target for cardioprotection.
The Hatter Cardiovascular Institute, University College London Hospital, 67 Chenies Mews, London WC1E 6HX, United Kingdom.
Sang-Ging
SG
Ong
Derek J
DJ
Hausenloy
D052242:Adiponectin / Q000502:physiology; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D015316:Genetic Therapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial; D060588:LIM Domain Proteins / Q000502:physiology; D035683:MicroRNAs / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011393:Procollagen-Proline Dioxygenase / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D037761:Sirtuins / Q000502:physiology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology
D052242:Adiponectin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C403807:LIMD1 protein, human; D035683:MicroRNAs; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D037761:Sirtuins