title: Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of HIF-prolyl 4-hydroxylases for treatment of ischemic diseases.
abstract: CONCLUSIONS
  In this review, we have discussed the efficacy and effect of small molecules that act as prolyl hydroxylase domain inhibitors (PHDIs). The use of these compounds causes upregulation of the pro-angiogenic factors and hypoxia inducible factor-1α and -2α (HIF-1α and HIF-2α) to enhance angiogenic, glycolytic, erythropoietic, and anti-apoptotic pathways in the treatment of various ischemic diseases responsible for significant morbidity and mortality in humans.
  
  
  BACKGROUND
  Sprouting of new blood vessels from the existing vasculature and surgical intervention, such as coronary bypass and stent insertion, have been shown to be effective in attenuating ischemia. However, the initial reentry of oxygen leads to the formation of reactive oxygen species that cause oxidative stress and result in ischemia/reperfusion (IR) injury. This apparent "oxygen paradox" must be resolved to combat IR injury. During hypoxia, decreased activity of PHDs initiates the accumulation and activation of HIF-1α, wherein the modulation of both PHD and HIF-1α appears as promising therapeutic targets for the pharmacological treatment of ischemic diseases.
  
  
  RESULTS
  Research on PHDs and HIFs has shown that these molecules can serve as therapeutic targets for ischemic diseases by modulating glycolysis, erythropoiesis, apoptosis, and angiogenesis. Efforts are underway to identify and synthesize safer small-molecule inhibitors of PHDs that can be administered in vivo as therapy against ischemic diseases.
  
  
  CONCLUSIONS
  This review presents a comprehensive and current account of the existing small-molecule PHDIs and their use in the treatment of ischemic diseases with a focus on the molecular mechanisms of therapeutic action in animal models.
authors.affiliation: 1 Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut Health Center , Farmington, Connecticut.
authors.forename: Vaithinathan
authors.initials: V
authors.lastname: Selvaraju
authors.forename: Narasimham L
authors.initials: NL
authors.lastname: Parinandi
authors.forename: Ram Sudheer
authors.initials: RS
authors.lastname: Adluri
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Goldman
authors.forename: Naveed
authors.initials: N
authors.lastname: Hussain
authors.forename: Juan A
authors.initials: JA
authors.lastname: Sanchez
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Maulik
mesh_terms: D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D064800:Prolyl-Hydroxylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D064800:Prolyl-Hydroxylase Inhibitors; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases