Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis

Objectives - Advanced glycation endproducts, AGEs, and its specific receptor, RAGE, are involved in diabetic vascular complications. Endogenous secretory RAGE, esRAGE, has been identified as an alternatively spliced form of RAGE, and shown to act as a decoy receptor for AGE. Here, we measured plasma esRAGE level with a recently developed enzyme-linked immunosorbent assay ( ELISA) and examined its association with atherosclerosis in age- and gender-matched 203 type 2 diabetic and 134 nondiabetic subjects. Methods and Results - Plasma esRAGE was inversely associated with carotid or femoral atherosclerosis, as quantitatively measured as intimal-medial thickness (IMT) by arterial ultrasound. Stepwise regression analyses revealed that plasma esRAGE was the third strongest and independent factor associated with carotid IMT, following age and systolic blood pressure. Plasma esRAGE was significantly lower in diabetic patients (0.176 +/- 0.092 ng/mL) than nondiabetic controls (0.253 +/- 0.111). Of note, in all, diabetic or nondiabetic group, plasma esRAGE was significantly and inversely correlated with components of the metabolic syndrome including body mass index, blood pressure, triglyceride, HbA1c, or an insulin resistance index. Stepwise regression analyses showed that body mass index or insulin resistance index was the major factor determining plasma esRAGE in all, nondiabetic or diabetic population. Conclusions - esRAGE is a novel and potential protective factor for the metabolic syndrome and atherosclerosis.