The physiology of endothelial xanthine oxidase: From urate catabolism to reperfusion injury to inflammatory signal transduction

Xanthine oxidoreductase (XOR) is a ubiquitous metalloflavoprotein that appears in two interconvertible yet functionally distinct forms: xanthine dehydrogenase (XD). which is constitutively expressed in vivo. and xanthine oxidase (XO). which is generated by the posttranslational modification of XD, either through the reversible. incremental thiol oxidation of sulfhydryl residues on XD or the irreversible proteolytic cleavage of a segment of XD which occurs at low oxygen tension and in the presence of several proinflammatory mediators. Functionally. both XD and XO catalyze the oxidation of purines to urate. However, whereas XD requires NAD(+) as an electron acceptor for these redox reactions. thereby,generating the stable product NADH. XO is unable to use NAD(+) as an electron acceptor, requiring instead the reduction of molecular oxygen for this purine oxidation and generating, the highly reactive superoxide free radical. Nearly 100 Years of study has documented the physiologic role of XD in urate catabolism. However. the rapid., posttranslational conversion of XD to the oxidant-generating form XO provides a possible physiologic mechanism for rapid. posttranslational. oxidant-mediated signaling. XO-generated reactive oxygen species (ROS) have been implicated in various clinicopathologic entities, including ischemia/reperfusion injury and multisystem organ failure. More recently, the concept of physiologic signal transduction mediated by ROS has been proposed, and the possibility of XD to XO conversion. with subsequent ROS generation, serving as the trigger of the microvascular inflammatory response in vivo has been hypothesized. This review presents the evidence and basis for this hypothesis.