Published online before print October 13, 2005, doi: 10.1161/01.ATV.0000190660.32863.cd
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© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Plasma Level of Endogenous Secretory RAGE Is Associated With Components of the Metabolic Syndrome and Atherosclerosis
From the Department of Metabolism, Endocrinology, and Molecular Medicine (H.K., T.S., H.Y., K. Motoyama, K. Mori, S.F., M.E., T.S., Y.N.), Osaka City University Graduate School of Medicine, Osaka, Japan; Daiichi Fine Chemical Co Ltd (H.T., H.M.), Takaoka, Japan; and the Department of Biochemistry and Molecular Vascular Biology (S.S., Y.Y., H.Y., T.W., H.Y.), Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Correspondence to Dr Hidenori Koyama, Department of Metabolism, Endocrinology and Molecular Medicine, (Second Department of Internal Medicine), Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail hidekoyama{at}med.osaka-cu.ac.jp
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Abstract |
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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.
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 show that plasma esRAGE was inversely and independently associated with carotid atherosclerosis or components of the metabolic syndrome, even in the absence of diabetes.
Key Words: pathophysiology • risk factors • type 2 diabetes
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Introduction |
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Under 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 and intracytoplasmic domains.11 esRAGE was found to be released outside from the cells, to bind AGE ligands, and to be capable of neutralizing AGE actions on endothelial cells in culture.11 In the present study, we measured plasma esRAGE level and examined its association with atherosclerosis in 203 diabetic and 134 nondiabetic subjects. We found that plasma esRAGE was inversely associated with carotid and femoral atherosclerosis. On note, plasma esRAGE levels were inversely associated with components of the metabolic syndrome; particularly body mass index, or insulin resistance index, even in subpopulation with or without diabetes.
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Methods |
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Study Subjects
This study was approved by the Ethical Committee at Osaka City University Graduate School of Medicine (approval No. 730). Diabetic (n=203) and nondiabetic (n=134) subjects were participants of a medical check program performed at the Diabetes Center in Osaka City University Hospital (Osaka, Japan) and the Osaka Health Promotion Center (Osaka, Japan), respectively, and informed consent was obtained from all subjects enrolled in the study. Clinical characteristics are summarized in Table 1. Type 2 diabetes was diagnosed by fasting plasma glucose >126 mg/dL (7 mmol/L), causal plasma glucose >200 mg/dL (11.1 mmol/L), or 2-hour plasma glucose >200 mg/dL during 75-gram oral glucose tolerance test, or previous therapy for diabetes. Diabetic patients with overt proteinuria were excluded. Among 134 nondiabetic individuals, 16 subjects were in the criteria of impaired glucose tolerance (IGT) by 75-gram oral glucose tolerance test. Hypertension was defined as a blood pressure >140/90 mm Hg or the use of agents for the treatment of hypertension. Hypercholesterolemia was defined as total cholesterol higher than 5.2 mmol/L or the use of any drugs for the treatment. No significant differences in age, gender distribution, body mass index, and systolic blood pressure between diabetic and nondiabetic groups. Significantly more diabetic patients (6.9%) had history of cardiovascular disease than nondiabetic subjects (1.5%) (Table 1). In diabetic group, 42 patients were treated with insulin and 98 patients were receiving sulfonylurea. To examine the association of plasma esRAGE with the metabolic syndrome, the patients with obesity accompanying at least 2 of the following 3 factors: 1) plasma triglycerides
150 mg/dL (1.680 mmol/L) or high-density lipoprotein (HDL) cholesterol <40 mg/dL (1.034 mmol/L) or receiving lipid-lowering therapy; 2) systolic blood pressure 130 mm Hg or diastolic blood pressure 85 mm Hg or receiving medication for the treatment of hypertension; 3) fasting plasma glucose 110 mg/dL (6.061 mmol/L) or defined diabetic patients. These were extracted according to the recently described criteria for a Japanese population, which was modified from the NCEP criteria.12 In this study, presence of obesity was defined by body mass index 25 kg/m2 as reported for Japanese population.13
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Ultrasonography
Ultrasonographic scanning of the carotid artery was performed by an ultrasonic phase-locked echotracking system, which was equipped with a high-resolution real-time 10-MHz liner scanner (ProSound II, Aloka Co Ltd). Participants were scanned in the supine position. The site of the most advanced atherosclerotic lesion in the right carotid or femoral artery was examined in the longitudinal and transverse projections to record the maximum intima-media thickness (IMT).14,15 A reproducibility found a between-sonographer coefficient of variation of 3.2% for diabetic subjects and 3.6% for nondiabetic subjects as previously described.14
Measurement of Plasma esRAGE
A recently developed enzyme-linked immunosorbent assay (ELISA) system, which detects esRAGE specifically, is described in detail elsewhere, and is now provided as a kit (Daiichi Fine Chemical Co Ltd, Takaoka, Japan). In brief, esRAGE from 20 µL of plasma was specifically detected by sandwich ELISA system using monoclonal antibody 278-13G4 coated on microtiter plates and rabbit esRAGE-specific polyclonal antibody conjugated with horseradish peroxidase. Monoclonal antibody 278-13G4 was raised against the purified recombinant human esRAGE protein, which recognizes 3 distinct alternative spliced form of RAGE in reducing condition in Western blot analyses: full-length, N-terminus truncated, and C-terminus truncated RAGE (esRAGE). The epitope recognized by this antibody was thus judged to reside on the common C-region–like domain. Rabbit esRAGE-specific polyclonal antibody was raised against the unique C-terminal 16-amino-acid peptide (amino acids 332 to 347; EGFDKVREAEDSPQHM)- keyhole limpet hemocyanin (KLH) conjugate and was confirmed to recognize the C-terminal region of esRAGE.11 AGE or S100 engagement of the amino-terminal V-region-like domain of esRAGE, therefore, would not interfere with those antibody bindings. The sensitivity of the assay was 0.05 ng/mL of sample solution, and linearity was obtained from 0.05 to 3.2 ng/mL. The within-day and between-day coefficient of variation (CV) examined at 3 different concentrations of esRAGE were <6.5% and <7.5%, respectively.
Biochemical Analyses
Serum levels of total cholesterol, triglycerides and HDL cholesterol were measured by enzymatic methods adapted to an autoanalyzer (Hitachi 7470; Hitachi, Tokyo, Japan). Non-HDL cholesterol was calculated by subtracting HDL cholesterol from total cholesterol. Plasma glucose levels were measured by the glucose oxidation method and hemoglobin A1c (HbA1c) by high-pressure liquid chromatography (normal range, 4.0% to 5.8%). For subjects not receiving insulin (diabetic: n=161, nondiabetic: n=134), insulin resistance was assessed with the homeostasis model assessment (HOMA) index, as defined by (fasting plasma insulin; µU/mL)x(fasting plasma glucose; mmol/L)/22.5.16 Plasma high-sensitivity C-reactive protein (hsCRP) levels were measured by N High Sensitivity CRP kit obtained from Dade Behring (Marburg, Germany). Urinary albumin excretion was defined as urinary albumin (mg)/urinary creatinine (mg).
Statistical Analyses
Statistical analyses were performed with the use of StatView V software (SAS Institute, Cary, NC). Student t test, ANOVA with multiple comparisons (Scheffe’s type) or 
2 test was performed for comparisons among groups. To evaluate the relation between the plasma esRAGE and other factors, simple or stepwise regression analyses were performed. Logarithmic-transformation of HOMA [log(HOMA)] was performed to achieve normal distribution and was used for regression analyses.16 P<0.05 or F-value >4.0 was considered significant.
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Results |
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Plasma esRAGE Is Inversely Associated With Carotid or Femoral Atherosclerosis
We first measured plasma esRAGE by recently developed ELISA system and examined their relationship with carotid atherosclerosis quantitatively determined by ultrasound. As shown in Figure 1, plasma esRAGE levels were inversely and significantly correlated with both carotid and femoral IMT. To examine if the inverse association between esRAGE and atherosclerosis was independent of the other clinical factors, stepwise multiple regression analyses were performed. As shown in Table 2
A, plasma esRAGE was the third strongest and independent factor associated with carotid IMT, following age and systolic blood pressure with first and second strongest determinants. For femoral artery IMT, only smoking and age were the factors independently associated. In this model, the association of plasma esRAGE with femoral artery IMT did not achieve statistically significant (F=2.48). In this study, diabetic subjects showed significantly higher carotid (0.948±0.497 versus 0.702±0.300, mean±SD, P<0.0001) or femoral IMT (1.157±0.767 versus 0.921±0.544, P=0.037) than nondiabetic subjects. When the subjects were divided into 3 groups (normal glycemic tolerance [NGT], IGT, and DM), carotid IMT of both IGT (1.197±0.417) and DM (0,948±0.497) group were significantly (P=0.0162 and P<0.0001, ANOVA with Scheffe’s multiple comparisons) higher than NGT group (0.675±0.270), as implicated that IGT itself can be a major risk factor for cardiovascular diseases.17,18 In nondiabetic subjects alone, inverse relation between plasma esRAGE and carotid (r=–0.245, P=0.0080) or femoral artery (r=0.278, P=0.0026) remained significant. These relations remain significant even when IGT subjects were excluded. In contrast, association of plasma esRAGE with carotid (r=0.007, P=0.9231) or femoral artery IMT (r=–0.048, P=0.4932) was not significant in diabetic patients alone.
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We next performed multiple logistic regression analyses of factors associated with the presence or absence of plaque in carotid or femoral artery (Table 2
B). In model 1 including age, gender (male), body mass index, smoking, systolic blood pressure, non-HDL cholesterol, HDL cholesterol, and HbA1c as variables, age, male, smoking, and HbA1c were identified as independent factors associated with presence of plaque. Interestingly, in model 2 adding plasma esRAGE levels to model 1 as variables, esRAGE was identified as an independent and significant factor associated with plaque presence, with the association of HbA1c being not significant any more. Thus, effects of diabetes or glycemic control on atherosclerosis could at least partly explained by the low plasma esRAGE levels.
Components of the Metabolic Syndrome Are Associated With Plasma esRAGE
Significant link between plasma esRAGE and atherosclerosis even in population without diabetes led us to explore factor(s) associated with plasma esRAGE. Mean plasma esRAGE levels were significantly lower in type 2 diabetic patients than nondiabetic subjects (Table 1). When the subjects were divided into 3 groups, NGT, IGT, and DM, subjects with both IGT (0.190±0.099 ng/mL) and DM (0.176±0.092) showed significantly (P=0.0266 and P<0.0001, respectively, ANOVA with multiple comparisons [Scheffe’s type]) lower plasma esRAGE than subjects with NGT (0.262±0.110). Female subjects (0.226±0.114) showed significantly (P=0.0040) higher plasma esRAGE than male subjects (0.192±0.099). Hypertensive patients (0.174±0.096) had significantly (P<0.0001) lower plasma esRAGE than nonhypertensive subjects (0.228±0.109). Presence of hypercholesterolemia (0.204±0.105 versus 0.191±0.099, P=0.3177) did not affect the levels of plasma esRAGE. Importantly, the subjects with metabolic syndrome (0.156±0.082) showed significantly (P<0.0001) lower plasma esRAGE levels than those without it (0.217±0.108). Thus, plasma esRAGE levels appear not solely associated with glycemic status, but with components of metabolic syndrome.
Simple regression analyses (Table 3) clearly showed that in all subjects, plasma esRAGE was inversely associated with components of metabolic syndrome, a complex set of risk factors, including insulin resistance, hypertension, glucose intolerance, and dyslipidemia, that dramatically increases cardiovascular risk.19 These include body mass index (Figure 2), systolic and diastolic blood pressure, decreased HDL cholesterol, serum triglycerides, glycemic status, and insulin resistance state (Figure 2). Importantly, these relations remained significant when the nondiabetic or diabetic subjects were separately analyzed (Table 3). Even when IGT subjects were excluded from the non-diabetes group, body mass index (r=–0.336, P=0.0002), systolic (r=–0.271, P=0.0029), diastolic blood pressure (r=–0.326, P=0.0003), triglyceride (r=–0.260, P=0.0061) and HbA1c (r=–0.225, P=0.0181) were still significantly associated with plasma esRAGE levels. Plasma esRAGE was significantly and inversely associated with serum hsCRP only in nondiabetic subjects. Age was also inversely related to plasma esRAGE in nondiabetic but not in diabetic subjects. Urinary albumin excretion was not significantly associated with plasma esRAGE in this study.
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Finally, stepwise multiple regression analyses were performed to examine if the relation of plasma esRAGE with components of the metabolic syndrome is independent of the other clinical factors (Table 4). The factors significantly associated with plasma esRAGE in simple regression analyses were included as variables. In all subjects, HbA1c, body mass index, male gender and age were selected as independent factors inversely associated with plasma esRAGE (Table 4A, Model 1). When body mass index was excluded from variables, insulin resistance index, HOMA, and systolic blood pressure were now selected as significant independent factors inversely associated with plasma esRAGE levels (Model 2). Furthermore, when both body mass index and HOMA were excluded (Model 3), another component of metabolic syndrome, serum triglycerides, was identified as an independent factor. Importantly, even in the nondiabetic (Table 4B) or diabetic (Table 4C) subgroup alone, either body mass index or insulin resistance index was also identified as a significant independent factor inversely associated with plasma esRAGE. Taken together, our data clearly indicate that plasma esRAGE is associated with components of the metabolic syndrome.
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Discussion |
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To the best of our knowledge, this is the first to measure plasma esRAGE in human plasma and demonstrate inverse associations between plasma esRAGE and several components of metabolic syndrome, including body mass index, insulin resistance index, blood pressure, hypertriglyceridemia, and impaired glycemic control. Plasma esRAGE is also inversely associated with the quantitatively determined atherosclerosis in the carotid and femoral arteries. Thus, plasma esRAGE is not only involved in pathophysiology of diabetic microangiopathy, but a potential factor protecting against metabolic syndrome and atherosclerosis.
The present study showed for the first time that plasma esRAGE is inversely associated with atherosclerosis in both carotid and femoral arteries as quantitatively determined by ultrasound. Our clinical data are in good agreement with the basic observations, in which augmentation of atherosclerosis in diabetic mice is inhibited by the competition of RAGE with sRAGE.7,10 Of note, significant inverse relation between plasma esRAGE and carotid or femoral artery was observed even in nondiabetic subjects alone. Moreover, plasma esRAGE appears to be already decreased in subjects with IGT, which has been shown to be a major risk factor for cardiovascular disease.17,18 Recently, Falconi et al20 measured plasma sRAGE levels in nondiabetic men, and showed that its levels are significantly lower in patients with angiographically proved coronary artery disease than age-matched healthy controls. Mean plasma sRAGE level in their healthy control is 1.335 ng/mL, which is approximately 5-fold higher than our plasma esRAGE levels in non-diabetic subjects (0.253±0.111 ng/mL). Because they measured total sRAGE, it could be possible that esRAGE constitutes part, but not all, of the sRAGE levels in human plasma. Indeed, recent study by Park et al showed a novel splice variant which is produced by circulating cells of the blood.21 The difference could also represent ethnic differences in esRAGE levels between Japanese and white Italian subjects. Even though we need to be careful to interpret the data, our findings suggest potential involvement of the RAGE system in progression of atherosclerosis and cardiovascular diseases even in nondiabetic population.
Our present results strongly suggest that plasma esRAGE is associated with components of metabolic syndrome or atherosclerosis in the absence of diabetes. Because RAGE ligands include proinflammatory proteins including S100/calgranulins3,22 and high-mobility group 1 (HMGB1) protein,23 inflammation may be a key factor linking RAGE system with metabolic syndrome or atherosclerosis. The newest version of response-to-injury hypothesis emphasizes that atherosclerosis is a multi-factorial inflammatory disease involving endothelial cells, vascular smooth muscle cells, mononuclear cells, growth factors and cytokines.24 Components of the metabolic syndrome and the metabolic syndrome itself are also associated with measures of inflammation, such as increased concentrations of C-reactive protein and decreased antiinflammatory molecule, adiponectin.19,25–27 This low-grade inflammation, which has been associated with an increased risk for atherosclerotic disease and diabetes,28,29 may provide a mechanism for the increased risk of these conditions experienced by individuals who have the metabolic syndrome. The potential role of RAGE in the metabolic syndrome is recently demonstrated by a link between a polymorphism of the RAGE gene and insulin resistance.30 Among RAGE ligand, AGE intake is shown to be associated with insulin resistance and atherosclerosis in mouse models.31,32
Plasma esRAGE was significantly and inversely associated with HbA1c only in nondiabetic, but not in diabetic population. Moreover, significant inverse correlation between plasma esRAGE and atherosclerotic arterial wall thickness was observed in nondiabetic subjects alone. Thus, our overall data suggest that plasma esRAGE is more closely associated with early stage of diabetes, such as metabolic syndrome, IGT or atherosclerosis, but not with advanced diabetic conditions. At present, it is not clear why plasma esRAGE is not inversely associated with glycemic control in diabetic subjects. Potential mechanism could be the influence of renal function or the presence of microangiopathy on plasma esRAGE. Yamamoto’s group observed strong positive relation of plasma esRAGE with serum creatinine (r=0.505, P<0.0001) or urinary albumin excretion (r=0.278, P=0.02) in type 1 diabetic patients (unpublished observation). Our diabetic population, not including patients with overt proteinuria, shows no significant correlation of plasma esRAGE with urinary albumin excretion. However, multiple regression analysis using age, gender, body mass index, systolic blood pressure, non-HDL cholesterol, HDL cholesterol, triglycerides, HbA1c and urinary albumin excretion as variables (R2=0.100, P=0.0239) showed that body mass index (ß=–0.222, P=0.0042), systolic blood pressure (ß=–0.167, P=0.0325) and urinary albumin excretion (ß=0.164, P=0.0307) were the independent factors significantly associated with plasma esRAGE levels. Although the underlying mechanism remains unclear, presence of renal microangiopathy appears to increase the plasma esRAGE, which makes the regulation of esRAGE in diabetes much complicated.
The body of work demonstrates that RAGE ligands are closely associated with variety of inflammatory legions. S100/calgranulins is upregulated in rheumatoid arthritis,33,34 inflammatory bowel disease,35 atherosclerosis5,36 and inflammatory arteritis.37 Plasma S100A12 is recently shown to be increased in diabetes with its level correlated with subclinical inflammation.38 HMGB1 is also shown to be involved in rheumatoid arthritis,39 and is capable of activating endothelium.40 Moreover, sRAGE successfully reduced inflammatory responses in many models.7,10,35,41–43 Using recently developed RAGE-depleted mice, Liliensiek et al44 showed that the absence of RAGE protects mice from lethal multibacterial peritonitis and sepsis caused by cecal ligation and puncture. All these findings strongly implicate RAGE signaling plays important roles in modulating local inflammation. Moreover, esRAGE is now shown to be expressed in wide variety of human tissues including vascular endothelium, pneumocytes, pancreatic beta cells, monocyte/macrophages, and various epithelial cells,45 many cells of which play pivotal roles in local inflammation. Even though the origin of cells determining plasma esRAGE is not clear, the association of plasma esRAGE with components of metabolic syndrome or atherosclerosis may be linked to inflammation-modulatory roles of esRAGE. Although the association between esRAGE and serum hsCRP is weak, further studies will be warranted to address this hypothesis, particularly examining inter-relationship between plasma esRAGE and RAGE-ligands involved in inflammation, including S100/calgranulins and HMGB1.
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Acknowledgments |
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This study was supported in part by grant-in-aid for scientific research (15590953 to H.K.) from the Japan Society for the Promotion of Science, by R&D, for the practical use of university-based technology, by matching government funds and private funds from the Ministry of Economy, Trade, and Industry of Japan (No. 0320003), and grants-in-aid for scientific research from the Japan Society for the Promotion of Science (No. 16570113 to T.W.).
Received June 8, 2005; accepted September 13, 2005.
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