Submitted November 30, 2007
Accepted February 27, 2008
HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak
Julio C. Morote-Garcia, Peter Rosenberger, Johannes Kuhlicke, and Holger K. Eltzschig*
Department of Anesthesiology and Intensive Care Medicine, Tuebingen University Hospital, Tuebingen, Germany
Department of Anesthesiology and Perioperative Medicine, Mucosal Inflammation Program, University of Colorado Health Science Center, Denver, CO, United States
* Corresponding author; email: holger.eltzschig{at}uchsc.edu.
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 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 (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 pharmacological inhibitors of AK in the treatment of conditions associated with hypoxia-induced vascular leakage (e.g. sepsis or acute lung injury).
