Explanations for conflicting results between different studies could be related to the demographic, genetic and health characteristics of the populations under investigation. of both the cleaved form of sRAGE and esRAGE [30]. Furthermore, sRAGE levels may be influenced by polymorphisms in other genes, for example in ADAM10 [45]. Finally, levels of both sRAGE isoforms are strongly affected by ethnicity, being lower in people from Afro-Caribbean and Hispanic origin than in Caucasians [26,30,35]. Other studies in patients with cardiometabolic conditions have shown that the concentration of sRAGE isoforms in blood can be influenced by therapeutic agents, including angiotensin receptor blockers (ARBs), angiotensin converting enzyme inhibitors, calcium channel antagonists, statins and thiazolidinediones (reviewed in Ref. [4]). ARBs were found to decrease sRAGE levels in angiotensin II-treated endothelial cells and in patients with essential hypertension [46]. Similarly, the calcium channel blocker azelnidipine was shown to reduce sRAGE in non-diabetic chronic nephropathy [47]. In contrast, statins and thiazolidinediones cause an increase in blood levels of both total sRAGE and esRAGE in type 2 diabetes [[48], [49], [50]]. Likewise, physical exercise has been reported to increase esRAGE levels in people at low/intermediate risk of cardiovascular disease (CVD) [51]. The detailed mechanisms underlying the different effects of these interventions are not known, though in the case of statins, these were reported to stimulate RAGE shedding by an ADAM10-mediated mechanism [52]. In addition, some of the drugs may affect sRAGE levels by inhibiting inflammation pathways [53] or by improving renal function [26,42]. 4.?The function of sRAGE The function that sRAGE plays in human biology has been the subject of substantial debate. A widely held view is that sRAGE fulfills a protective anti-inflammatory role by acting as a decoy receptor, binding RAGE ligands and thus blocking their interaction with membrane-bound RAGE. In support of this possibility experiments in animals models of diabetes and/or CVD have shown that administration of recombinant sRAGE improves vascular and renal IGF2R function, reduces myocardial ischaemic injury, as well as atherosclerosis, vascular inflammation and other diabetic complications L-Stepholidine (Reviewed in Ref. [1]). In addition, sRAGE administration has been shown to decrease inflammation in an animal model of multiple sclerosis [54]. In considering the function of sRAGE as a decoy receptor, it is relevant to note that in RAGE-deficient mice em (Ager /em em ?/? /em ) sRAGE can still block certain inflammation responses, probably by preventing putative RAGE ligands from interacting with other receptors [55]. Aside from behaving as a decoy receptor sRAGE may also act as a ligand of the leukocyte integrin MAC-1 and transduce pro-inflammatory L-Stepholidine signals, thereby inducing leukocyte recruitment to sites of injury or L-Stepholidine inflammation [56,57]. Consistent with this role, bacterial burden and neutrophil infiltration was shown to worsen following sRAGE administration in a mouse model of bacterial lung infection, suggesting that in acute settings sRAGE may actually sustain inflammation [58]. In contrast, sRAGE has been shown to prevent leukocyte recruitment in a diabetic mouse model of acute peritonitis [59]. sRAGE forms have been measured in humans in search for associations with disease states or their risk factors (reviewed in Refs. [60,61]). Many of these studies reported sRAGE levels to be lower in people with cardiometabolic and other chronic conditions than in healthy subjects, providing further support to the notion that sRAGE fulfills a protective role [60]. Nevertheless, positive associations between sRAGE levels and prevalent ill health have also been described, most notably in the contexts of diabetes and renal disease [60,61], and more recently also in frailty [62]. These contrasting lines of evidence suggest that the status of sRAGE in human pathophysiology deserves further examination. In this regard, an alternative view argues that the amount of sRAGE generated in vivo may not be sufficient to compete effectively with membrane-bound RAGE for ligand binding, particularly in situations where RAGE itself is also upregulated [2]. Furthermore, an increase in total circulating levels of sRAGE may reflect increased RAGE activation and autoinduction [18,63], and in this way attest to a condition of low-grade chronic inflammation, rather than to a healthy state. 5.?The relationship between sRAGE and oxidative stress Several lines of evidence indicate that RAGE activation L-Stepholidine by AGEs and other ligands cause oxidative stress [8,9,64,65]. Consistent with this notion and in keeping with the decoy receptor concept described above, sRAGE has been shown to reduce markers of oxidative stress when administered to animal models of vascular dysfunction [66,67]. Hence, sRAGE is sometimes attributed an anti-oxidant role. This view has been also supported by reports from small clinical studies of atherosclerotic vascular disease or cardiometabolic disorders describing inverse correlations between sRAGE levels and makers of oxidative stress [[68], [69], [70], [71], [72], [73]], and by a study describing a positive correlation with plasma anti-oxidant defenses in Alzheimer’s disease patients [74]. However, it should be noted that.