Translation of ischemic preconditioning to the patient: prolyl hydroxylase inhibition and hypoxia inducible factor-1 as novel targets for stroke therapy.
Effective therapies for stroke must interdict multiple parallel and sequential pathophysiological events. A paradigm which offers insight into multivalent but thoughtfully coordinated protective programs is ischemic preconditioning. A central hypothesis of our group and others is that pharmacological agents that activate programs of gene expression normally induced by ischemic preconditioning will be effective agents for the prevention and treatment of stroke. Inhibitors of a class of enzymes, the hypoxia inducible factor-1 (HIF-1) prolyl hydroxylases stabilize the transcriptional activator HIF-1 and activate target genes involved in compensation for ischemia, including erythropoeitin (Epo) and vascular endothelial growth factor (VEGF). Here, we review evidence suggesting that the HIF-1 prolyl hyroxylases are inhibited during ischemic preconditioning and that pharmacological inhibitors of these enzymes are viable targets for stroke therapy.
Department of Neurology and Neuroscience, Burke/Cornell Medical Research Institute, Weill Medical College of Cornell, White Plains, NY 10605, USA. rratan@caregroup.harvard.edu
Rajiv R
RR
Ratan
Ambreena
A
Siddiq
Leila
L
Aminova
Philipp S
PS
Lange
Brett
B
Langley
Issam
I
Ayoub
JoAnn
J
Gensert
Juan
J
Chavez
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology; D015687:Cell Hypoxia; D004268:DNA-Binding Proteins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006706:Homeostasis; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019194:Ischemic Preconditioning; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000502:physiology*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D020521:Stroke / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D014157:Transcription Factors / Q000502:physiology*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D014157:Transcription Factors; D011393:Procollagen-Proline Dioxygenase