Soluble RAGE and Atherosclerosis in Youth With T1D
Advanced glycation end products (AGEs) have been implicated in the pathogenesis of both microvascular complications and accelerated atherosclerosis in type 1 diabetes (T1D). A proposed mechanism for the deleterious effect of AGEs is engagement of the receptor for AGEs, RAGE, which is a multiligand transmembrane receptor in the immunoglobulin superfamily present on the surface of various cell types in atherosclerotic lesions. Two of the AGEs that potentially bind to RAGE are carboxymethyllysine (CML) and methylglyoxal-derived hydroimidazolone-1 (MG-H1). Receptor binding leads to activation of monocytes and the vascular endothelium and increases inflammation in the vessel wall. A mouse cell model indicates that RAGE also mediates AGE-induced macrophage migration.
RAGE has two soluble forms prevalent in human plasma. One created as the membrane bound receptor is cleaved by metalloproteinases, and the other produced by alternative splicing of the RAGE gene. The latter is known as endogenous secretory RAGE (esRAGE), and together they constitute plasma soluble RAGE (sRAGE). Estimates indicate that esRAGE accounts for 20–50 % of sRAGE.
It has been postulated that both soluble variants of RAGE work as decoys for AGEs, reducing RAGE signaling and inflammation. In a mouse model, treatment with intraperitoneal sRAGE suppressed the accelerated atherosclerosis of diabetes. This suggests that high levels of sRAGE protect against the atherogenic effect of AGEs. Studies in T1D have, however, shown conflicting results. Levels of soluble variants of RAGE both lower and higher than controls have been demonstrated. Previously, Katakami et al. have found an inverse association between levels of esRAGE and carotid intima media thickness (cIMT) both cross-sectionally and longitudinally in young adults. Nin et al., however, showed a positive association between sRAGE and cardiovascular events and all-cause mortality. The seemingly contradictory results might be due to the different ethnic origin of the study populations, but more likely reflect the complexity of the regulation of the AGE-RAGE-sRAGE and AGE-RAGE-esRAGE axes. This implies that AGEs or sRAGE alone may not be particularly informative as biomarkers, and an AGE/sRAGE ratio has been proposed as an improvement.
In this study, we aimed to investigate longitudinally whether higher levels of soluble variants of RAGE protect against atherosclerosis development in young patients with T1D compared to healthy controls.
Background
Advanced glycation end products (AGEs) have been implicated in the pathogenesis of both microvascular complications and accelerated atherosclerosis in type 1 diabetes (T1D). A proposed mechanism for the deleterious effect of AGEs is engagement of the receptor for AGEs, RAGE, which is a multiligand transmembrane receptor in the immunoglobulin superfamily present on the surface of various cell types in atherosclerotic lesions. Two of the AGEs that potentially bind to RAGE are carboxymethyllysine (CML) and methylglyoxal-derived hydroimidazolone-1 (MG-H1). Receptor binding leads to activation of monocytes and the vascular endothelium and increases inflammation in the vessel wall. A mouse cell model indicates that RAGE also mediates AGE-induced macrophage migration.
RAGE has two soluble forms prevalent in human plasma. One created as the membrane bound receptor is cleaved by metalloproteinases, and the other produced by alternative splicing of the RAGE gene. The latter is known as endogenous secretory RAGE (esRAGE), and together they constitute plasma soluble RAGE (sRAGE). Estimates indicate that esRAGE accounts for 20–50 % of sRAGE.
It has been postulated that both soluble variants of RAGE work as decoys for AGEs, reducing RAGE signaling and inflammation. In a mouse model, treatment with intraperitoneal sRAGE suppressed the accelerated atherosclerosis of diabetes. This suggests that high levels of sRAGE protect against the atherogenic effect of AGEs. Studies in T1D have, however, shown conflicting results. Levels of soluble variants of RAGE both lower and higher than controls have been demonstrated. Previously, Katakami et al. have found an inverse association between levels of esRAGE and carotid intima media thickness (cIMT) both cross-sectionally and longitudinally in young adults. Nin et al., however, showed a positive association between sRAGE and cardiovascular events and all-cause mortality. The seemingly contradictory results might be due to the different ethnic origin of the study populations, but more likely reflect the complexity of the regulation of the AGE-RAGE-sRAGE and AGE-RAGE-esRAGE axes. This implies that AGEs or sRAGE alone may not be particularly informative as biomarkers, and an AGE/sRAGE ratio has been proposed as an improvement.
In this study, we aimed to investigate longitudinally whether higher levels of soluble variants of RAGE protect against atherosclerosis development in young patients with T1D compared to healthy controls.