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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2140-2147. Prepublished online as a Blood First Edition Paper on June 8, 2007; DOI 10.1182/blood-2007-02-073254. This Article Full Text (PDF) All Versions of this Article: blood-2007-02-073254v1 110/6/2140    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hsieh, M. M Articles by Tisdale, J. F Search for Related Content PubMed PubMed Citation Articles by Hsieh, M. M Articles by Tisdale, J. F Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 8, 2007 Accepted June 1, 2007 HIF-prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and fetal hemoglobin expression in rhesus macaques Matthew M Hsieh, N Seth Linde, Aisha Wynter, Mark Metzger, Carol Wong, Ingrid Langsetmo, Al Lin, Reginald Smith, Griffin P Rodgers, Robert E Donahue, Stephen J Klaus, and John F Tisdale* Molecular & Clinical Hematology Branch (MCHB), National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), NIH, Bethesda, MD, United States National Heart, Lung, & Blood Institute (NHLBI), NIH, Rockville, MD, United States Cell Biology, FibroGen, Inc, San Francisco, CA, United States * Corresponding author; email: johntis{at}mail.nih.gov. Hypoxia-inducible factor (HIF) pathway is crucial in mitigating the deleterious effects of oxygen deprivation. HIF-alpha is an essential component of the oxygen-sensing mechanisms and under normoxic conditions is targeted for degradation via hydroxylation by HIF-prolyl hydroxylases. Several HIF-prolyl hydroxylase inhibitors (PHI) induced erythropoietin (Epo) expression in vitro and in mice, with peak Epo expression ranging from 5.6 to 207 fold above control animals. Furthermore, several PHIs induced fetal hemoglobin (HbF) expression in primary human erythroid cells in vitro as determined by flow cytometry. One PHI, FG-2216, was further tested in a non-human primate model without and with chronic phlebotomy. FG-2216 was orally bioavailable and induced significant and reversible Epo induction in vivo (82 to 309 fold at 60 mg/kg). Chronic oral dosing in male rhesus macaques was well tolerated, significantly increased erythropoiesis, and prevented anemia induced by weekly phlebotomy. Furthermore, modest increases in HbF containing red cells and reticulocytes were demonstrated by flow cytometry, though significant increases in HbF were not demonstrated by HPLC. HIF PHIs represent a novel class of molecules with broad potential clinical application for congenital and acquired anemias. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: A pill for some anemias? Derek A. Persons Blood 2007 110: 1709. [Full Text] [PDF] This article has been cited by other articles: Y. A. Minamishima, J. Moslehi, R. F. Padera, R. T. Bronson, R. Liao, and W. G. Kaelin Jr. A Feedback Loop Involving the Phd3 Prolyl Hydroxylase Tunes the Mammalian Hypoxic Response In Vivo Mol. Cell. Biol., November 1, 2009; 29(21): 5729 - 5741. [Abstract] [Full Text] [PDF] J.-Y. Jeong, G. Hoxhaj, A. L. Socha, A. J. Sytkowski, and L. Feldman An Erythropoietin Autocrine/Paracrine Axis Modulates the Growth and Survival of Human Prostate Cancer Cells Mol. Cancer Res., July 1, 2009; 7(7): 1150 - 1157. [Abstract] [Full Text] [PDF] P. Sathyanarayana, E. Houde, D. Marshall, A. Volk, D. Makropoulos, C. Emerson, A. Pradeep, P. J. Bugelski, and D. M. Wojchowski CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools Blood, May 14, 2009; 113(20): 4955 - 4962. [Abstract] [Full Text] [PDF] J. Schodel, B. Klanke, A. Weidemann, B. Buchholz, W. Bernhardt, M. Bertog, K. Amann, C. Korbmacher, M. Wiesener, C. Warnecke, et al. HIF-Prolyl Hydroxylases in the Rat Kidney: Physiologic Expression Patterns and Regulation in Acute Kidney Injury Am. J. Pathol., May 1, 2009; 174(5): 1663 - 1674. [Abstract] [Full Text] [PDF] C. Rosenberger, S. Rosen, A. Shina, U. Frei, K.-U. Eckardt, L. A. Flippin, M. Arend, S. J. Klaus, and S. N. Heyman Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney Nephrol. Dial. Transplant., November 1, 2008; 23(11): 3472 - 3478. [Abstract] [Full Text] [PDF] V. H. Haase Hemoglobin in the Kidney: Breaking with Traditional Dogma J. Am. Soc. Nephrol., August 1, 2008; 19(8): 1440 - 1441. [Full Text] [PDF] M.-C. Lauzier, G. A. Robitaille, D. A. Chan, A. J. Giaccia, and D. E. Richard (2R)-[(4-Biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS), a Matrix Metalloprotease Inhibitor, Is a Novel and Potent Activator of Hypoxia-Inducible Factors Mol. Pharmacol., July 1, 2008; 74(1): 282 - 288. [Abstract] [Full Text] [PDF] K. Takeda, H. L. Aguila, N. S. Parikh, X. Li, K. Lamothe, L.-J. Duan, H. Takeda, F. S. Lee, and G.-H. Fong Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins Blood, March 15, 2008; 111(6): 3229 - 3235. [Abstract] [Full Text] [PDF] Y. A. Minamishima, J. Moslehi, N. Bardeesy, D. Cullen, R. T. Bronson, and W. G. Kaelin Jr Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure Blood, March 15, 2008; 111(6): 3236 - 3244. [Abstract] [Full Text] [PDF]

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