Role of endogenous secretory RAGE (esRAGE) in defending against plaque formation induced by oxidative stress in type 2 diabetic patients Francesco Piarulli a, * , Annunziata Lapolla a , Eugenio Ragazzi b , Angela Susana a , Annalisa Sechi a , Laura Nollino a , Chiara Cosma a , Domenico Fedele a , Giovanni Sartore a a Department of Medicine e DIMED, University of Padova, Via dei Colli 4, 35143 Padova, Italy b Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy article info Article history: Received 20 January 2012 Received in revised form 18 October 2012 Accepted 21 October 2012 Available online 9 November 2012 Keywords: Type 2 diabetes Oxidative stress Atherosclerotic plaque esRAGE abstract Objectives: This study was conducted to examine the relationship between endogenous secretory receptors for advanced glycation end products (esRAGE) and oxidative stress in type 2 diabetic patients (T2DM) with/without advanced macro-angiopathy. Methods: Sixty-one T2DM were assessed for glycemic control, lipid profile, AGEs, carboxymethyl-lysine (CML), soluble receptor for advanced glycation end products (sRAGE), esRAGE and vitamin E levels, and underwent echo-color-Doppler of the abdominal aorta and aorto-iliac tree, carotid and lower limb arteries to check for evidence of plaques. Results: AGEs and CML levels were significantly higher in T2DM with plaques than in those without (P ¼ 0.0156 and P ¼ 0.007, respectively) despite a comparable metabolic control and history of disease. EsRAGE and vitamin E levels were lower in T2DM with than in those without plaques (P < 0.0001), while no differences were observed as regards sRAGE levels. Considering all T2DM, univariate regression analysis showed a positive correlation between esRAGE and vitamin E (r ¼ 0.456, P < 0.001), and a negative correlation between esRAGE and AGEs (r ¼0.284, P < 0.05). After dividing patients by the presence/absence of plaques, esRAGE only correlated directly with vitamin E (r ¼ 0.563, P < 0.01) and CML (r ¼ 0.479, P < 0.05) in patients without plaques. Conclusions: This is the first study to establish a relationship between esRAGE and oxidative stress and/or antioxidant power, suggesting that esRAGE upregulation might be part of the cell’s antioxidative defenses against plaque forming as a result of oxidative stress in the T2DM phenotype (cases with a more efficient esRAGE production being better protected). Ó 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Hyperglycemia can induce a non-enzymatic glycation of proteins, generating Amadori products that undergo further complex reactions leading to the formation of advanced glycation end products (AGEs) [1], which have a key role in the pathogenesis of the macro- and microvascular complications of diabetes, in both type 1 and type 2 patients [2]. AGEs contribute to endothelial damage via several mechanisms, including intracellular protein modifications, the formation of cross-links in the extracellular matrix, and interaction with the receptor for AGEs (RAGE) [3]. This receptor is a multiligand member of an immunoglobulin superfamily of cell-surface molecules [4] engaging AGEs and leading to cellular signaling, including nuclear factor kB (NF-kB) activation, increased cytokine and adhesion molecule expression, the induction of oxidative stress [5], and an increase in cytosolic reactive oxygen species [6]. Carboxymethyl-lysine (CML) is a product of glycoxidation and the well-characterized main AGE structure; it is recognized by RAGE and capable of directly activating the AGE-RAGEeNF-NF-kB axis [7]. It has been demonstrated that the CML formed by protein-bound glycated lysine oxidation is a major AGE in vascular lesions and its level is associated with macrovascular complications in diabetic patients [8]. The soluble RAGE (sRAGE) isoform expresses the cellular concentration of RAGE and reflects the total pool of soluble RAGE in plasma, which includes several variants. Endogenous soluble RAGE Abbreviations: AGEs, advanced glycation end products; sRAGE, soluble receptor for advanced glycation end products; esRAGE, endogenous secretory receptor for advanced glycation end products; T2DM, type 2 diabetic patients; IMT, intimae media thickness; CML, carboxymethyl-lysine. * Corresponding author. Tel.: þ39 0498216848; fax: þ39 0498216838. E-mail address: francesco.piarulli@unipd.it (F. Piarulli). Contents lists available at SciVerse ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis 0021-9150/$ e see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.050 Atherosclerosis 226 (2013) 252e257