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J. Biol. Chem., Vol. 280, Issue 50, 41732-41743, December 16, 2005

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Hypoxia-inducible Factor Prolyl 4-Hydroxylase Inhibition

A TARGET FOR NEUROPROTECTION IN THE CENTRAL NERVOUS SYSTEM^*

Ambreena Siddiq¶, Issam A. Ayoub, Juan C. Chavez¶||, Leila Aminova, Sapan Shah, Joseph C. LaManna||, Stephanie M. Patton**, James R. Connor**, Robert A. Cherny, Irene Volitakis, Ashley I. Bush, Ingrid Langsetmo¶¶, Todd Seeley¶¶, Volkmar Gunzler¶¶, and Rajiv R. Ratan¶1

From the Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, Burke/Cornell Medical Research Institute, White Plains, New York 10605, the ^¶Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, the ^||Department of Anatomy and Neurology, Case Western Reserve University, Cleveland, Ohio 44106, the ^**Department of Neurosurgery, George M. Leader Family Laboratory for Alzheimer Disease Research, Penn State College of Medicine, Hershey, Pennsylvania 17033, the Department of Pathology, the University of Melbourne, Mental Health Research Institute of Victoria, Parkville 3052, Australia, Laboratory of Oxidation Biology, Genetics and Aging Research Unit, Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, and ^¶¶Fibrogen, Inc., South San Francisco, California 94080

Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases are a family of iron- and 2-oxoglutarate-dependent dioxygenases that negatively regulate the stability of several proteins that have established roles in adaptation to hypoxic or oxidative stress. These proteins include the transcriptional activators HIF-1 and HIF-2. The ability of the inhibitors of HIF prolyl 4-hydroxylases to stabilize proteins involved in adaptation in neurons and to prevent neuronal injury remains unclear. We reported that structurally diverse low molecular weight or peptide inhibitors of the HIF prolyl 4-hydroxylases stabilize HIF-1 and up-regulate HIF-dependent target genes (e.g. enolase, p21^waf1/cip1, vascular endothelial growth factor, or erythropoietin) in embryonic cortical neurons in vitro or in adult rat brains in vivo. We also showed that structurally diverse HIF prolyl 4-hydroxylase inhibitors prevent oxidative death in vitro and ischemic injury in vivo. Taken together these findings identified low molecular weight and peptide HIF prolyl 4-hydroxylase inhibitors as novel neurological therapeutics for stroke as well as other diseases associated with oxidative stress.

Received for publication, May 5, 2005 , and in revised form, October 13, 2005.

^* This work was supported by National Institutes of Health Grants NS39170, NS40591, and NS46239 (to R. R. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Burke/Cornell Medical Research Institute, 785 Mamaroneck Ave., White Plains, NY 10605. Tel.: 914-597-2851; Fax: 914-597-2225; E-mail: rratan{at}burke.org or rrr2001{at}cornell.med.edu.

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