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 (0.176Ϯ0.092 ng/mL) than nondiabetic controls (0.253Ϯ0.111). 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. Key Words: pathophysiology Ⅲ risk factors Ⅲ type 2 diabetes U nder hyperglycemic conditions, endogenous nonenzymatic glycoxidation of proteins and lipids leads to the formation of heterogeneous products, collectively termed advanced glycation end products (AGEs). 1 AGE engagement of cell surface the receptor for AGE (RAGE) results in cellular signaling including activation of nuclear factor-B, increased expression of cytokines and adhesion molecules, and induction of oxidative stress. 2,3 Transgenic mice overexpressing human RAGE in vascular cells developed advanced nephropathy when they were made diabetic. 4 Thus, the AGE-RAGE system has been thought to play a pivotal role in the development of diabetic microvascular complications.Accumulating evidence suggests that RAGE is also involved in macrovascular complications in diabetes. 5,6 RAGE expression is shown to be upregulated in atherosclerotic plaques of diabetic animals. 7 Some of the human studies also implicate the involvement of RAGE in diabetic vasculopathy. 8,9 Moreover, the group of Stern and Schmidt has shown that augmentation of atherosclerosis in diabetic mice is inhibited by the competition of RAGE with its soluble truncated form termed soluble RAGE (sRAGE), lacking the transmembrane and cytoplasmic domains, produced by recombinant gene engineering. 7,10 Recently, an endogenous secretory RAGE (esRAGE) has been identified as a novel splice variant that directs the synthesis of RAGE proteins carrying all of the extracellular domains but devoid of the transmembrane...

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In addition to this unique pathway, FGFR3 also links to GRB2⅐Sos complex via the adapter protein Shc. Furthermore, activated FGFR3 was not able to induce dissociation of GRB2⅐Sos complex following Sos phosphorylation. In summary, FGFR3 signaling pathway utilizes two GRB2-containing complexes; Shc⅐GRB2⅐Sos and 80K-H⅐pp66⅐GRB2⅐Sos; these two complexes may alternatively link FGFG3 to mitogen-activated protein kinase. Finally, activated FGFR3 was also found to result in phosphorylation of phospholipase C-␥ but reduced phosphorylation of c-Src.

Background-Recent genetic animal models reveal important roles of platelet P-selectin on progression of atherosclerosis.In the present study, we examine the relation between platelet P-selectin expression and atherosclerotic parameters in 517 subjects. Methods and Results-Unrelated subjects (nϭ517; 235 male and 282 female), including 187 with type 2 diabetes, 184with hypertension, and 366 with hyperlipidemia, were enrolled in the study. P-selectin expression was determined by whole-blood flow cytometry. Arterial stiffness (stiffness index ␤) and arterial wall thickness (intima-media thickness [IMT]) were determined by carotid ultrasound. P-selectin expression was significantly and positively correlated with carotid IMT and stiffness index ␤. Multiple regression analyses showed that the association of the percentage of P-selectin-positive platelets with carotid IMT was independent of other clinical factors. Moreover, the percentage of P-selectin-positive platelets was higher in subjects with carotid plaque and was an independent factor associated with occurrence of carotid plaque analyzed by multiple logistic regression analysis. Finally, the percentage of P-selectinpositive platelets was positively associated with age, body mass index, systolic and diastolic blood pressure, and HbA1c and inversely associated with HDL cholesterol. Conclusions-Platelet P-selectin is independently associated with atherosclerotic arterial wall changes in human subjects.(Circulation. 2003;108:524-529.)

Angiogenic response is impaired in diabetes. Here, we examined the involvement of receptor for advanced glycation end products (RAGE) in diabetes-related impairment of angiogenesis in vivo. Angiogenesis was determined in reconstituted basement membrane protein (matrigel) plugs containing vascular endothelial growth factor (VEGF) implanted into nondiabetic or insulin-deficient diabetic wild-type or RAGE ؊/؊ mice. The total, endothelial, and smooth muscle (or pericytes) cells in the matrigel were significantly decreased in diabetes, with the regulation dependent on RAGE. In the matrigel, proangiogenic VEGF expression was decreased, while antiangiogenic thrombospondin-1 was upregulated in diabetic mice, regardless of the presence of RAGE. In wild-type mice, proliferating cell nuclear antigen (PCNA)-positive cells in the matrigel were significantly less in diabetic than in nondiabetic mice, while the numbers of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells were significantly higher. This alteration in PCNA-and TUNEL-positive cells in diabetes was not observed in RAGE ؊/؊ mice. Similarly, the percentage of nuclear factor B-activated cells is enhanced in diabetes, with the regulation dependent on the presence of RAGE. Importantly, adenovirus-mediated overexpression of endogenous secretory RAGE, a decoy receptor for RAGE, restores diabetes-associated impairment of angiogenic response in vivo. Thus, RAGE appears to be involved in impairment of angiogenesis in diabetes, and blockade of RAGE might be a potential therapeutic target. Diabetes 55: [2245][2246][2247][2248][2249][2250][2251][2252][2253][2254][2255] 2006

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Receptor for advanced glycation end products (RAGE) has been shown to be involved in adiposity as well as atherosclerosis even in nondiabetic conditions. In this study, we examined mechanisms underlying how RAGE regulates adiposity and insulin sensitivity. RAGE overexpression in 3T3-L1 preadipocytes using adenoviral gene transfer accelerated adipocyte hypertrophy, whereas inhibitions of RAGE by small interfering RNA significantly decrease adipocyte hypertrophy. Furthermore, double knockdown of high mobility group box-1 and S100b, both of which are RAGE ligands endogenously expressed in 3T3-L1 cells, also canceled RAGE-medicated adipocyte hypertrophy, implicating a fundamental role of ligands–RAGE ligation. Adipocyte hypertrophy induced by RAGE overexpression is associated with suppression of glucose transporter type 4 and adiponectin mRNA expression, attenuated insulin-stimulated glucose uptake, and insulin-stimulated signaling. Toll-like receptor (Tlr)2 mRNA, but not Tlr4 mRNA, is rapidly upregulated by RAGE overexpression, and inhibition of Tlr2 almost completely abrogates RAGE-mediated adipocyte hypertrophy. Finally, RAGE−/− mice exhibited significantly less body weight, epididymal fat weight, epididymal adipocyte size, higher serum adiponectin levels, and higher insulin sensitivity than wild-type mice. RAGE deficiency is associated with early suppression of Tlr2 mRNA expression in adipose tissues. Thus, RAGE appears to be involved in mouse adipocyte hypertrophy and insulin sensitivity, whereas Tlr2 regulation may partly play a role.

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