Published Online
on October 7, 2004

A more recent version of this article appeared on November 1, 2004

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Submitted on July 12, 2004
Accepted on August 5, 2004

Translation of Ischemic Preconditioning to the Patient. Prolyl Hydroxylase Inhibition and Hypoxia Inducible Factor-1 as Novel Targets for Stroke Therapy

Rajiv R. Ratan MD, PhD^*; Ambreena Siddiq PhD; Leila Aminova PhD; Philipp S. Lange MD; Brett Langley PhD; Issam Ayoub MD; JoAnn Gensert PhD; and Juan Chavez PhD

From the Department of Neurology and Neuroscience, Burke/Cornell Medical Research Institute, Weill Medical College of Cornell, White Plains, NY.

^* To whom correspondence should be addressed. E-mail: rratan{at}caregroup.harvard.edu.

Abstract--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.

Key words: acute care • hypoxia • ischemia • stroke • transcription

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