Biomedical subjects

Sho-ichi Yamagishi

Publications and source records attributed to Sho-ichi Yamagishi.

At least 19 recordsLinked to original sources

PubMed2007

Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in diabetic subjects with coronary artery disease.

BACKGROUND: Advanced glycation end products (AGEs)-receptor (RAGE) axis is implicated in diabetic vascular complication. Since a soluble form of RAGE (sRAGE) could be generated from the cleavage of cell surface RAGE in endothelial cells (ECs), serum sRAGE levels may be elevated in diabetes consequent to EC damage. In this study, we examined whether sRAGE levels were elevated in type 2 diabetic patients compared with non-diabetic healthy subjects. METHODS: Serum sRAGE levels were examined in 75 Japanese type 2 diabetic patients (29 men and 46 women; mean age 66 +/- 11 years) and 75 age- and sex-matched non-diabetic healthy control subjects. We explored the association between sRAGE levels and coronary artery disease (CAD) in diabetic patients. RESULTS: Serum sRAGE levels were significantly higher in diabetic patients than in non-diabetic subjects (965.3 +/- 544.2 vs 415 +/- 150.4 pg/mL, p < 0.001). In the univariate analysis, diastolic blood pressure (inversely), LDL cholesterol, triglycerides, HDL cholesterol, hemoglobin A(1c), and creatinine were significantly associated with sRAGE. After performing multivariate analyses, the presence of diabetes (p < 0.0001) was a sole independent determinant of sRAGE. Furthermore, there was a significant difference in sRAGE levels between diabetic patients with CAD and those without CAD (1680.6 +/- 891.1 vs 855.2 +/- 372.1 pg/mL, p < 0.001). Multiple stepwise regression analysis revealed that sRAGE and creatinine levels were independent determinants of CAD. CONCLUSIONS: The present study demonstrated that serum sRAGE levels were significantly higher in type 2 diabetic patients than in non-diabetic subjects and positively associated with the presence of CAD.

Aged↗

PubMed2006

Pitavastatin inhibits lysophosphatidic acid-induced proliferation and monocyte chemoattractant protein-1 expression in aortic smooth muscle cells by suppressing Rac-1-mediated reactive oxygen species generation.

Lysophosphatidic acid (LPA), a product generated during oxidative modification of low-density lipoprotein (LDL) and a major lipid extracted from human atherosclerotic plaques, has been shown to elicit smooth muscle cell (SMC) proliferation and inflammation, thereby being involved in atherogenesis. Recently, statins, an inhibitor of 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase, have been reported to reduce the risk of cardiovascular events and slows the progression of atherosclerosis, at least partly, via pleiotropic effects. However, the effect of statin on the LPA-signaling in SMCs remains to be elucidated. In this study, we investigated whether and how pitavastatin could inhibit the LPA-induced proliferation and monocyte chemoattractant protein-1 (MCP-1) expression in cultured human aortic SMCs. LPA dose-dependently increased intracellular reactive oxygen species (ROS) generation in SMCs, which was blocked by diphenylene iodonium (DPI), an inhibitor of NADPH oxidase or pitavastatin. The anti-oxidative property of pitavastatin was prevented by simultaneous treatment of geranylgeranyl pyrophosphate. Furthermore, overexpression of dominant negative Rac-1 mutant was found to inhibit the LPA-induced ROS generation in SMCs. LPA induced Rac-1 activation in SMCs, which was suppressed by pitavastatin or LPA receptor antagonist. Pitavastatin, DPI, and an anti-oxidant N-acetylcysteine inhibited the LPA-induced proliferation and MCP-1 gene expression in SMCs. These results suggest that pitavastatin could block the LPA-induced proliferation and MCP-1 expression in SMCs by suppressing Rac-1-mediated NADPH oxidase-dependent ROS generation. Our present study provides a novel beneficial aspect of pitavastatin; pitavastatin may act as a blocker of the LPA-signaling in SMCs.

Antioxidants↗

PubMed2006

Advanced glycation end products attenuate cellular insulin sensitivity by increasing the generation of intracellular reactive oxygen species in adipocytes.

Advanced glycation end products (AGE) have been observed in various pathological conditions especially in diabetes mellitus. However, it is unclear as to whether AGE are involved in insulin resistance in adipose tissues. In this study, we examined the effects of AGE on insulin sensitivity in adipocytes by examining the effects of AGE and its mechanisms on the glucose uptake in adipocytes and adipocyte differentiation. Glucose-, glyceraldehyde-, or glycolaldehyde-derived AGE inhibited the differentiation of 3T3-L1 cells. These AGE also inhibited the glucose uptake in the absence or presence of insulin, which were completely prevented by antibody against AGE or receptor for AGE (RAGE). The AGE increased the intracellular reactive oxygen species (ROS) generation in 3T3-L1 adipocytes, and the effects of AGE on glucose uptake were completely reversed by the treatment with an anti-oxidant, N-acetylcysteine. The AGE also induced the expression of monocyte chemoattractant protein-1, which has been implicated in the development of obesity-associated glucose intolerance, in 3T3-L1 adipocytes. Our present study suggests that AGE-RAGE interaction inhibits the glucose uptake through the overgeneration of intracellular ROS, thus indicating that it is involved in the development of obesity-related insulin resistance.

3T3-L1 Cells↗

PubMed2006

Elevated circulating oxidized LDL levels in Japanese subjects with the metabolic syndrome.

In the present study, we examined the relationship between circulating oxidized low-density lipoprotein (LDL) and the metabolic syndrome in Japanese patients. Subjects who had no histories of coronary or peripheral artery disease and were taking no medications (n=119; age 57+/-10 years; male/female, 90:29) underwent a complete history and physical examination, determination of blood chemistries and oxidized LDL levels. In stepwise regression analysis, triglycerides (p=0.0001) and HDL-cholesterol (p=0.0493, inversely) were independently correlated to oxidized LDL levels. Furthermore, a significant association (p<0.0001) was found between circulating oxidized LDL levels and the accumulation of the number of the components of the metabolic syndrome. Oxidized LDL levels were one of the independent determinants of intima-media thickness of the common carotid artery, a surrogate marker of atherosclerosis. The present study reveals that circulating oxidized LDL levels are strongly associated with the metabolic syndrome. Our results suggest that elevation of oxidized LDL may be a possible molecular link between accelerated atherosclerosis and the metabolic syndrome in Japanese subjects.

Adult↗

PubMed2006

Susceptibility of brain microvascular endothelial cells to advanced glycation end products-induced tissue factor upregulation is associated with intracellular reactive oxygen species.

There is accumulating evidence that advanced glycation end products (AGEs) are relevant to the formation of vascular complications in diabetes mellitus. The aim of this study was to investigate whether AGEs have a significant effect on tissue factor (TF) expression in brain microvascular endothelial cells compared with that in other arterial endothelial cells. Cultured bovine brain microvascular endothelial cells (BBMECs) and aortic endothelial cells (BAECs) were incubated in medium containing glyceraldehyde-derived AGE (glycer-AGE). TF mRNA expression, protein expression, and activity were measured at multiple time points after glycer-AGE incubation. Participation of reactive oxygen species (ROS) in the effect of glycer-AGE on TF expression was investigated by treatment with a free radical scavenger, edaravone, and intracellular ROS measurements with dihydroethidium (DHE). Basic TF mRNA expression was greater in BBMECs than in BAECs. Glycer-AGE significantly upregulated TF mRNA expression in both cells, and the upregulation was more prominent in BBMECs than in BAECs. TF protein expression and activity were also upregulated with a pattern of being greater in BBMECs than in BAECs. Edaravone significantly attenuated the AGE-induced upregulation of TF mRNA expression, protein expression, and activity. Intracellular ROS levels measured with DHE-stained fluorescent intensity were significantly upregulated by glycer-AGE with a pattern of being greater in BBMECs than in BAECs. AGE-induced ROS upregulation was attenuated by edaravone like AGE-induced TF upregulation. These results suggest that brain microvascular endothelial cells are more susceptible to AGE-induced TF upregulation than aortic endothelial cells, and that this susceptibility is associated with levels of intracellular ROS.

Animals↗

PubMed2006

Pigment epithelium-derived factor (PEDF) blocks the interleukin-6 signaling to C-reactive protein expression in Hep3B cells by suppressing Rac-1 activation.

There is a growing body of evidence to show that that C-reactive protein (CRP), an acute phase reactant, is one of the most valuable predictors of future cardiovascular events. Since CRP proteins directly contribute to the development and progression of atherosclerosis as well, reduction of CRP levels may be a novel therapeutic target for the treatment of cardiovascular disease. In this study, we examined whether pigment epithelium-derived factor (PEDF) could block the interleukin-6-induced CRP expression in cultured human hepatoma cells and the way that it might achieve this effect. PEDF inhibited the IL-6-induced CRP expression in Hep3B cells at both mRNA and proteins levels. PEDF suppressed the intracellular reactive oxygen species generation in IL-6-exposed Hep3B cells. Anti-oxidants mimicked the effects of PEDF. PEDF was also found to inhibit the IL-6-elicited Rac-1 activation, whereas dominant-negative Rac-1 dose-dependently decreased the CRP mRNA levels. PEDF blocked the IL-6-induced STAT3 phosphorylations and NF-kappaB p65 activity in Hep3B cells. Our present study suggests that PEDF could be one of the potent suppressors of CRP production by the liver and may play a protective role against atherosclerosis.

Antibodies, Monoclonal↗

PubMed2006

Molecular mechanism for elevation of asymmetric dimethylarginine and its role for hypertension in chronic kidney disease.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. ADMA is generated by protein methyltransferase (PRMT) and is metabolized mainly by dimethylarginine dimethylaminohydrolase (DDAH). ADMA levels are reported to increase in patients with chronic kidney disease (CKD), thereby playing a role in the pathogenesis of accelerated atherosclerosis in this population. However, the precise mechanism underlying ADMA accumulation in these patients is not fully understood. This study investigated the molecular mechanism for the elevation of ADMA levels in CKD, using a rat remnant kidney model that represents progressive CKD. After male Sprague-Dawley rats underwent baseline measurement of BP and renal function, 5/6 subtotal nephrectomy (5/6Nx) and 4/6 nephrectomy were performed. Plasma and urinary levels of ADMA and symmetric dimethylarginine, an inert isomer of ADMA, were measured by HPLC. Expression levels of PRMT genes and DDAH proteins were analyzed by semiquantitative reverse transcription-PCR and Western blotting, respectively. Plasma ADMA levels were elevated in the Nx groups in proportion to the degree of nephrectomy despite marked increases in renal clearance of ADMA. In contrast, renal clearance of symmetric dimethylarginine was decreased and its plasma levels were increased in the Nx groups. Furthermore, both liver and kidney gene expression of PRMT was increased, whereas DDAH protein expression was decreased in the 5/6Nx group. Plasma ADMA levels were correlated with systolic BP levels. Moreover, adenovirus-mediated DDAH gene transfer into the 5/6Nx rats prevented the elevation of BP levels, which was associated with the reduction of plasma and urinary ADMA levels. The results presented here suggest that decreased DDAH levels as well as increased PRMT gene expression could cause the elevation of plasma ADMA levels, thereby eliciting hypertension in CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of hypertension-related vascular injury in CKD.

Adenoviridae↗

PubMed2006

Pigment epithelium-derived factor (PEDF) prevents diabetes- or advanced glycation end products (AGE)-elicited retinal leukostasis.

Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, suggesting that PEDF may protect against proliferative diabetic retinopathy. However, a role for PEDF in early diabetic retinopathy remains to be elucidated. Leukocyte adhesion to retinal capillary endothelium (leukostasis) is a critical event in early diabetic retinopathy, whose process is mainly mediated by intercellular adhesion molecule-1 (ICAM-1). We investigated here whether PEDF could prevent diabetes- or advanced glycation end products (AGE)-elicited retinal leukostasis by suppressing ICAM-1 expression. Immunohistochemistry of 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, showed intense staining in the nuclei of cells in the inner and outer plexiform layers of streptozotocin-induced diabetic rat retinas. Administration of PEDF or pyridoxal phosphate, an AGE inhibitor, decreased retinal levels of 8-OHdG and subsequently suppressed ICAM-1 gene expression and retinal leukostasis in diabetic rats. Further, intravenous administration of AGE to normal rats increased ICAM-1 gene expression and retinal leukostasis, which were blocked by PEDF. PEDF also inhibited the AGE-induced T cell adhesion to microvascular endothelial cells by suppressing ICAM-1 expression. These results demonstrated that PEDF inhibited diabetes- or AGE-elicited retinal leukostasis by suppressing ICAM-1. Our present study suggests that PEDF may play a protective role against early diabetic retinopathy by attenuating the deleterious effect of AGE.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2006

Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression.

Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis, suggesting that loss of PEDF contributes to proliferative diabetic retinopathy. However, the role of PEDF against retinal vascular hyperpermeability remains to be elucidated. We investigated here whether and how PEDF could inhibit the advanced glycation end product (AGE) signaling to vascular hyperpermeability. Intravenous administration of AGEs to normal rats not only increased retinal vascular permeability by stimulating vascular endothelial growth factor (VEGF) expression but also decreased retinal PEDF levels. Simultaneous treatments with PEDF inhibited the AGE-elicited VEGF-mediated permeability by down-regulating mRNA levels of p22(phox) and gp91(phox), membrane components of NADPH oxidase, and subsequently decreasing retinal levels of an oxidative stress marker, 8-hydroxydeoxyguanosine. PEDF also inhibited the AGE-induced vascular hyperpermeability evaluated by transendothelial electrical resistance by suppressing VEGF expression. Furthermore, PEDF decreased reactive oxygen species (ROS) generation in AGE-exposed endothelial cells by suppressing NADPH oxidase activity via down-regulation of mRNA levels of p22(PHOX) and gp91(PHOX). This led to blockade of the AGE-elicited Ras activation and NF-kappaB-dependent VEGF gene induction in endothelial cells. These results indicate that the central mechanism for PEDF inhibition of the AGE signaling to vascular permeability is by suppression of NADPH oxidase-mediated ROS generation and subsequent VEGF expression. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy.

Adult↗

PubMed2006

Pigment epithelium-derived factor (PEDF) inhibits advanced glycation end product (AGE)-induced C-reactive protein expression in hepatoma cells by suppressing Rac-1 activation.

Serum levels of advanced glycation end products (AGEs) are associated with an acute phase reactant, C-reactive proteins (CRP) in diabetic patients. However, whether AGEs could directly stimulate hepatic CRP production remains to be elucidated. We found here that AGEs upregulated CRP mRNA levels in cultured Hep3B cells via Rac-1 activation, which was blocked by pigment epithelium-derived factor (PEDF). Our present study suggests that AGEs are one of the potent inducers of CRP and that PEDF may work as an anti-inflammatory agent against AGEs in the liver.

C-Reactive Protein↗

PubMed2006

Pigment-epithelium-derived factor (PEDF) inhibits angiotensin-II-induced vascular endothelial growth factor (VEGF) expression in MOLT-3 T cells through anti-oxidative properties.

Angiotensin II (Ang II), the dominant effector of the renin-angiotensin system, elicits numerous inflammatory-proliferative responses, thereby being involved in angiogenesis. T cells play an important role in angiogenesis as well by delivering vascular endothelial growth factor (VEGF) to inflammatory sites. Since we have previously shown that pigment-epithelium-derived factor (PEDF) blocks the Ang II signaling in endothelial cells, we studied here whether PEDF could inhibit the Ang-II-induced VEGF expression in MOLT-3 T and examined the potential mechanism of PEDF inhibitory effects. Ang II significantly up-regulated VEGF mRNA levels in MOLT-3 T cells, which was inhibited by PEDF or olmesartan, an Ang II type 1 receptor blocker. PEDF blocked the Ang-II-induced reactive oxygen species (ROS) generation in MOLT-3 T cells. Furthermore, H(2)O(2) was found to up-regulate VEGF mRNA levels in MOLT-3 T cells in a dose-dependent manner. These results demonstrate that PEDF could inhibit the Ang-II-induced VEGF expression in MOLT-3 T cells via suppression of ROS generation. Blockade by PEDF of VEGF expression in T cells may become a novel therapeutic target for pathological angiogenesis.

Angiotensin II↗

PubMed2006

Positive association of serum levels of advanced glycation end products with thrombogenic markers in humans.

Advanced glycation end products (AGEs) are elevated in diabetes. We have demonstrated that AGEs trigger thrombogenic responses in cultured cells. We investigated here whether serum AGE levels were positively correlated with thrombogenic markers in humans. Data for fasting serum AGE levels of 186 nondiabetic subjects were obtained from a general population in Japan. We measured body mass index, blood pressure, total cholesterol, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides, fasting plasma glucose, glycosylated hemoglobin A(1c), insulin, creatinine, uric acid, high-sensitive C-reactive protein, plasminogen activator inhibitor 1 (PAI-1), and fibrinogen. Uni- and multivariate analyses were applied for the determinants of serum AGE levels. The average AGE levels were 4.11 +/- 0.74 U/mL in males and 4.10 +/- 0.93 U/mL in females. In the univariate analysis, PAI-1 (P < .05) and fibrinogen (P < .05) were significantly associated with AGE levels. After performing multivariate analyses, PAI-1 (P < .05) and fibrinogen (P < .05) still remained significant independently. In conclusion, the present study is the first demonstration that PAI-1 and fibrinogen levels were positively associated with serum AGE levels. Advanced glycation end products may be associated with thrombogenesis in humans.

Aged↗

PubMed2006

Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects.

The advanced glycation end products (AGEs)-receptor for AGE (RAGE) axis is implicated in diabetic vascular complications. Administration of soluble form of RAGE (sRAGE) to mice has been shown to block the AGE-elicited tissue damage by acting as a decoy. These observations suggest that endogenous sRAGE may capture and eliminate circulating AGEs and decrease its serum levels. However, because AGEs up-regulate tissue RAGE expression and endogenous sRAGE could be generated from the cleavage of cell surface RAGE, sRAGE may be positively, rather than inversely, associated with circulating AGEs by reflecting tissue RAGE expression. In this study, we investigated the association of sRAGE with serum levels of AGEs in humans. Data for fasting serum sRAGE and AGE levels of 184 nondiabetic subjects were obtained from a general population in Japan. We also measured body mass index (BMI), waist circumference, blood pressure, and blood biochemistries in this population. Uni- and multivariate analyses were applied for the determinants of serum sRAGE levels. The average sRAGE levels were 0.40 +/- 0.17 ng/mL in males and 0.43 +/- 0.14 ng/mL in females, respectively. In the univariate analysis, BMI (P < .05, inversely), waist circumference (P < .05, inversely), AGEs (P < .05), and alcohol intake (P < .05, inversely) were significantly associated with sRAGE levels. After performing multivariate analyses, BMI (P < .05, inversely) and AGEs (P < .05) still remained significant independently. The present study is the first demonstration that serum sRAGE levels were positively associated with circulating AGEs in the nondiabetic general population. Endogenous sRAGE levels are elevated in parallel with serum AGE levels.

Aged↗

PubMed2006

Low-density lipoprotein subfractions and the prevalence of silent lacunar infarction in subjects with essential hypertension.

Recent lipid research has focused on low-density lipoprotein (LDL) subfractions as new markers for cardiovascular risk. However, the clinical significance of measurement of LDL subfractions in subjects with essential hypertension is yet to be established. We studied the association between the prevalence of silent lacunar infarction (SLI) and LDL subfractions in patients with essential hypertension. We performed brain MRI to detect SLI and measured LDL subfractions in 100 asymptomatic non-diabetic middle-aged subjects with essential hypertension (mean age, 62 years). We fractionated LDL into three parts, LDL-1, LDL-2, and LDL-3, with LDL-3 being the oxidized subfraction. Of the 100 study subjects, 24 (24%) had one or more SLIs, while the remaining 76 (76%) were considered as a non-SLI group. The LDL-3 levels were significantly higher in the SLI group than in the non-SLI group (8.3 +/- 4.4 mg/dl vs. 6.3 +/- 2.0 mg/dl, p = 0.006). Multiple logistic regression analysis showed that LDL-3 levels alone were an independent predictor of SLI (odds ratio [OR]: 1.380; 95% confidence interval [CI]: 1.113-1.663; p = 0.003). When subjects were divided into quartiles based on LDL-3 levels, the prevalence of SLI was significantly higher in the highest LDL-3 level group than in the lowest LDL-3 level group (p = 0.0036). The present study suggests that LDL-3 levels are associated with the prevalence of SLI in subjects with essential hypertension.

Adult↗

PubMed2006

Atorvastatin and diabetic vascular complications.

Statins inhibit 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme for cholesterol synthesis, and share the common mechanism of lowering circulating levels of low-density lipoprotein cholesterol. Among various statins, atorvastatin is the most widely used statin for the treatment of hypercholesterolemia. Recent clinical trials show that atorvastatin reduces the risk of cardiovascular events and slows the progression of atherosclerosis in patients with coronary artery diseases. Further, intensive therapy with atorvastatin is also associated with an early clinical benefit in patients with acute coronary syndrome. These observations support the concept that beyond lipid-lowering effects of atorvastatin, that is, pleiotropic effects, could contribute at least in part to cardiovascular event reduction. Diabetic vascular complication is a leading cause of end-stage renal failure, acquired blindness, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. However, whether atorvastatin therapy decreases the risk for the development and progression of diabetic vascular complications and the way that it might achieve these effects are not fully elucidated. In this paper, we focus on diabetic vascular complications and review the efficacy and safety of atorvastatin in the treatment of these devastating disorders. We further discuss here the possible vasculoprotective properties of atorvastatin in patients with diabetes.

Anticholesteremic Agents↗

PubMed2006

Pleiotropic effects of nifedipine on atherosclerosis.

Impaired endothelial cell (EC) growth and function have been proposed to be an initial event that leads to the development of atherosclerosis. There is a growing body of evidence that atherosclerosis is an inflammatory-fibroproliferative disease, and ECs are target for cytokines and growth factors released during inflammation. Recently, nifedipine, one of the most widely used dihydropyridine-based calcium antagonists (DHPs) for treatments of patients with hypertension, was shown to inhibit vascular inflammation and subsequently improve endothelial function in many cardiovascular diseases, thus slowing the development and progression of atherosclerosis. However, the molecular mechanisms underlying this are not fully understood, because ECs do not possess voltage-operated L-type calcium channels. In this review, we discuss the pleiotropic effects of nifedipine on atherosclerosis, especially focusing on its anti-oxidative properties.

Animals↗

PubMed2006

Cardiovascular disease in diabetes.

Diabetes is associated with a marked increase in the risk of atherosclerotic vascular disorders, including coronary, cerebrovascular, and peripheral artery disease. Cardiovascular disease (CVD) could account for disabilities and high mortality rates in patients with diabetes. In this paper, we review the molecular mechanisms for accelerated atherosclerosis in diabetes, especially focusing on postprandial hyperglycemia, advanced glycation end products (AGEs) and the renin-angiotensin system. We also discuss here the potential therapeutic strategy that specifically targets CVD in patients with diabetes.

Animals↗

PubMed2006

Role of advanced glycation end products (AGEs) in thrombogenic abnormalities in diabetes.

Accelerated atherosclerosis and microvascular complications are perhaps the leading cause of coronary heart disease, blindness and renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Several thrombogenic abnormalities have been shown to play a central role in the pathogenesis of these devastating complications. However, the molecular mechanism for thrombogenic diathesis in diabetes is not fully elucidated. A recent clinical study, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, has revealed that the reduction in the risk of progressive retinopathy and nephropathy resulting from intensive therapy in patients with type 1 diabetes persist for at least several years, despite increasing hyperglycemia. Further, intensive therapy during the DCCT resulted in decreased progression of carotid intima-media thickness six years after the end of the trial as well. These clinical studies strongly suggest that so-called 'hyperglycemic memory' causes chronic abnormalities in diabetic vessels that are not easily reversed, even by subsequent, relatively good control of blood glucose. Among various biochemical pathways activated under diabetes, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory 'hyperglycemic memory'. In this review, we discuss the role of AGEs in thrombogenic abnormalities in diabetes.

Animals↗