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Blood, 15 June 2008, Vol. 111, No. 12, pp. 5571-5580. Prepublished online as a Blood First Edition Paper on February 28, 2008; DOI 10.1182/blood-2007-11-126763. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-11-126763v1 111/12/5571    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Morote-Garcia, J. C. Articles by Eltzschig, H. K. Search for Related Content PubMed PubMed Citation Articles by Morote-Garcia, J. C. Articles by Eltzschig, H. K. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY HIF-1–dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak Julio C. Morote-Garcia1, Peter Rosenberger1, Johannes Kuhlicke1, and Holger K. Eltzschig1,2 1 Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Tübingen, Germany; and 2 Mucosal Inflammation Program, Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Science Center, Denver Extracellular adenosine has been implicated in vascular adaptation to hypoxia. Based on the observation that increases in intracellular adenosine can effectively elevate extracellular adenosine, we studied the contribution of adenosine kinase (AK, intracellular conversion of adenosine to adenosine monophosphate [AMP]) to vascular adenosine responses. Initial in vitro studies of ambient hypoxia revealed prominent repression of endothelial AK transcript (85% ± 2% reduction), protein, and function. Transcription factor binding assays and hypoxia inducible factor 1- (HIF-1) loss- and gain-of-function studies suggested a role for HIF-1 in transcriptional repression of AK. Moreover, repression of AK by ambient hypoxia was abolished in conditional HIF-1 mutant mice in vivo. Studies of endothelial barrier function revealed that inhibition or siRNA repression of AK is associated with enhanced adenosine-dependent barrier responses in vitro. Moreover, in vivo studies of vascular barrier function demonstrated that AK inhibition with 5'-iodotubericidin (1 mg/kg prior to hypoxia) significantly attenuated hypoxia-induced vascular leakage in multiple organs and reduced hypoxia-associated increases in lung water. Taken together, our data reveal a critical role of AK in modulating vascular adenosine responses and suggest pharmacologic inhibitors of AK in the treatment of conditions associated with hypoxia-induced vascular leakage (eg, sepsis or acute lung injury). CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Damage control by hypoxia-inhibited AK Michail V. Sitkovsky Blood 2008 111: 5424-5425. [Full Text] [PDF] This article has been cited by other articles: S. P. Hilchey, J. J. Kobie, M. R. Cochran, S. Secor-Socha, J.-C. E. Wang, O. Hyrien, W. R. Burack, T. R. Mosmann, S. A. Quataert, and S. H. Bernstein Human Follicular Lymphoma CD39+-Infiltrating T Cells Contribute to Adenosine-Mediated T Cell Hyporesponsiveness J. Immunol., November 15, 2009; 183(10): 6157 - 6166. [Abstract] [Full Text] [PDF] T. Eckle, M. Koeppen, and H. K. Eltzschig Role of Extracellular Adenosine in Acute Lung Injury Physiology, October 1, 2009; 24(5): 298 - 306. [Abstract] [Full Text] [PDF] S. Hatfield, B. Belikoff, D. Lukashev, M. Sitkovsky, and A. Ohta The antihypoxia-adenosinergic pathogenesis as a result of collateral damage by overactive immune cells J. Leukoc. Biol., September 1, 2009; 86(3): 545 - 548. [Abstract] [Full Text] [PDF] L. Bautista, M. J. Castro, J. Lopez-Barneo, and A. Castellano Hypoxia Inducible Factor-2{alpha} Stabilization and Maxi-K+ Channel {beta}1-Subunit Gene Repression by Hypoxia in Cardiac Myocytes: Role in Preconditioning Circ. Res., June 19, 2009; 104(12): 1364 - 1372. [Abstract] [Full Text] [PDF] H. K. Eltzschig, D. Kohler, T. Eckle, T. Kong, S. C. Robson, and S. P. Colgan Central role of Sp1-regulated CD39 in hypoxia/ischemia protection Blood, January 1, 2009; 113(1): 224 - 232. [Abstract] [Full Text] [PDF] M. V. Sitkovsky, J. Kjaergaard, D. Lukashev, and A. Ohta Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia Clin. Cancer Res., October 1, 2008; 14(19): 5947 - 5952. [Abstract] [Full Text] [PDF] T. Eckle, L. Fullbier, A. Grenz, and H. K. Eltzschig Usefulness of pressure-controlled ventilation at high inspiratory pressures to induce acute lung injury in mice Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L718 - L724. [Abstract] [Full Text] [PDF]

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