Apelin/APJ signaling suppresses the pressure ulcer formation in cutaneous ischemia-reperfusion injury mouse model

Abstract

Several studies have demonstrated potential roles for apelin/ApJ signaling in the regulation of oxidative stress associated with ischemia-reperfusion (i/R) injury in several organs. objective was to assess the role of apelin/ApJ signaling in the development of pressure ulcers (pUs) formation after cutaneous i/R injury in mice. We identified that cutaneous I/R injury increased the expression of apelin in the skin at I/R site. Administration of apelin significantly inhibited the formation of PUs. The reductions of blood vessels, hypoxic area and apoptosis in i/R site were inhibited by apelin injection. oxidative stress signals in OKD48 mice and the expressions of oxidative stress related genes in the skin were suppressed by apelin injection. H 2 o 2 -induced intracellular ROS and apoptosis in endothelial cells and fibroblasts were suppressed by apelin in vitro. Furthermore, MM07, biased agonist of APJ, also significantly suppressed the development of PUs after cutaneous I/R, and the inhibitory effect of MM07 on PUs formation was higher than that in apelin. We conclude that apelin/ApJ signaling may inhibit cutaneous i/R injuryinduced pUs formation by protecting the reduction of vascularity and tissue damage via suppression of oxidative stress. Exogenous application of apelin or MM07 might have therapeutic potentials against the development of pUs.Pressure ulcers (PUs) are one of the common skin diseases which usually occur elder people and patients with perceptual or movement disorder. In addition, the patients with PUs sometimes cause fatal outcome by local and systemic infections. There has long been considered that the pathogenesis of PUs was associated with tissue damage caused by external force and ischemia. However, there has been increasing evidence that cutaneous ischemia-reperfusion (I/R) is important in the pathogenesis of PUs 1-3 . I/R injury is defined as cellular injury caused by the reperfusion of blood to previously ischemic tissue 4,5 . It is described that reperfusion of blood into the hypoxic tissue triggers off adverse events, including thrombosis and capillary narrowing which lead to vasculopathy, infiltration of inflammatory cells, production of proinflammatory cytokines and the apoptosis of resident cells and necrosis of tissues 6 . I/R injury causes multiple diseases, such as vascular infarction or spasm of brain, heart, kidney and skin. Reactive oxygen species (ROS), such as H 2 O 2 and NO, are also known as a key player that exacerbate the tissues damage caused by I/R injury 7 .Apelin, an endogenous ligand of G protein-coulpled receptor APJ (putative receptor protein related to the angiotensin receptor AT1) 8,9 has multiple functions in the regulation of cardiovascular hemostasis, angiogenesis and adipose tissue function via apelin/APJ signaling 10-13 . APJ is expressed ubiquitously, especially in endothelial cells and vascular smooth muscle cells 8,9,11,12 . Furthermore, recent studies demonstrated that apelin/APJ signaling prevented oxidative stress, resulting in the inhibition of diabetic...

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