Hypoxia-Inducible Factor-1α–Dependent Protection from Intestinal Ischemia/Reperfusion Injury Involves Ecto-5′-Nucleotidase (CD73) and the A2B Adenosine Receptor

Abstract

Intestinal ischemia/reperfusion injury (IR) is characterized by intermittent loss of perfusion to the gut, resulting in dramatic increases in morbidity and mortality. Based on previous studies indicating an anti-inflammatory role for hypoxia-inducible factor (HIF)-1–elicited enhancement of extracellular adenosine production via ecto-5′-nucleotidase (CD73) and signaling through the A2B adenosine receptor (A2BAR), we targeted HIF-1 during IR using pharmacological or genetic approaches. Initial studies with pharmacological HIF activation indicated attenuation of intestinal injury with dimethyloxallyl glycine (DMOG) treatment during murine IR. Although DMOG treatment was associated with induction of CD73 transcript and protein, DMOG protection was abolished in cd73−/− mice. Similarly, DMOG treatment enhanced A2BAR transcript and protein levels, whereas DMOG protection was abolished in A2BAR−/− mice. Finally, studies of mice with conditional HIF-1α deletion in intestinal epithelia or pharmacological inhibition of HIF-1 with 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin revealed enhanced tissue injury during IR. These studies indicated a tissue-protective role of HIF-dependent enhancement of intestinal adenosine generation and signaling during intestinal IR.