Roles of Advanced Glycation Endoproducts(AGE) and Receptor for AGE on Vascular Smooth Muscle Cell Growth.

Wang, Ruojiao; Kudo, Mitsuhiro; Yokoyama, Munehiro; Asano, Gorō

doi:10.1272/jnms.68.472

Cited by 22 publications

(18 citation statements)

References 22 publications

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“…Wang, et al have demonstrated that the AGEs-RAGEs interaction in vascular smooth muscle cells, in addition to growth factors induced by AGEs, contributes to the stimulatory effect of diabetes on vascular smooth muscle cell proliferation which can accelerate atherosclerosis. 15) Aso, et al measured the serum concentrations of AGEs in type 2 DM patients and proposed that they were associated with the development of CAD as well as diabetic retinopathy and nephropathy. 16) Therefore, it is reasonable to speculate that there is at least one common pathway in the development of diabetic retinopathy and diabetic atherosclerotic lesions.…”

Section: Discussionmentioning

confidence: 99%

Retinopathy Is Related to the Angiographically Detected Severity and Extent of Coronary Artery Disease in Patients With Type 2 Diabetes Mellitus

et al. 2005

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SUMMARYDiabetic retinopathy (DR) is an early and frequent marker of other vascular complications of diabetes and its relation with coronary ischemia is known. The aim of the present study was to evaluate the association between DR and indices of coronary artery disease (CAD) severity and extent determined by coronary angiography.Sixty-nine diabetic patients undergoing coronary angiography for suspected CAD were evaluated. The severity and extent of CAD were scored from coronary angiograms by using 3 scores. Retinopathy was graded by fundus examination.There were differences in the severity score, extent score, number of vessels with disease, duration of diabetes, diabetes therapy, history of previous myocardial infarction (MI), and serum creatinine level among patients with and without DR. CAD severity was associated with the presence of DR (r: 0.53, P < 0.001), grade of DR (r: 0.52, P < 0.001), duration of diabetes (r: 0.28, P: 0.019), history of previous MI (r: 0.36, P: 0.002); and serum creatinine level (r: 0.24, P: 0.049) where the presence of DR was the only independent factor related to the severity score in multivariate analysis (r: 0.48, P < 0.001). The parameters related to the extent score were the presence of DR (r: 0.50, P < 0.001); grade of DR (r: 0.48, P < 0.001); previous MI (r: 0.37, P: 0.002) and age of the patient (r: 0.26, P: 0.033). Factors independently related to the extent score in multivariate analysis were the presence of DR (r: 0.37, P: 0.001), previous MI (r: 0.30, P: 0.006), and age of the patient (r: 0.22, P: 0.003).Among diabetics who are suspected of having CAD, those with retinopathy have more diffuse and severe coronary atherosclerosis, compared with diabetics without retinopathy. This cannot be explained by a longer duration or inferior control of the disease. (Int Heart J 2005; 46: 639-646)

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Section: Discussionmentioning

confidence: 99%

Retinopathy Is Related to the Angiographically Detected Severity and Extent of Coronary Artery Disease in Patients With Type 2 Diabetes Mellitus

et al. 2005

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“…There may also be species-dependent differences in SMC responses to AGEs. Thus, glycated albumin increases proliferation of rat [39,40] and rabbit [41] SMCs. In other studies, AGE-BSA did not stimulate proliferation of pig or rabbit SMCs [42,43].…”

Section: Rage Ligands Do Not Stimulate Human Smc Proliferationmentioning

confidence: 91%

Oleate, not ligands of the receptor for advanced glycation end-products, promotes proliferation of human arterial smooth muscle cells

et al. 2003

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Aims/hypothesis. Diabetes accelerates cardiovascular disease caused by atherosclerosis. Accordingly, diabetes accelerates atherosclerotic lesion progression and increases arterial smooth muscle cell proliferation. We hypothesized that diabetes can exert growth-promoting effects on smooth muscle cells via increased advanced glycation end-products or by dyslipidaemia. Methods. Primary human arterial smooth muscle cells were stimulated with advanced glycation end-products, other ligands of the receptor for advanced glycation end-products or fatty acids common in triglycerides. Cell proliferation was measured as DNA synthesis, cell cycle distribution and cell number. Effects of oleate on cellular phospholipids, diacylglycerol, triglycerides and cholesterol esters were analyzed by thin-layer chromatography, and oleate accumulation into diacylglycerol was confirmed by gas chromatography. Results. Human arterial smooth muscle cells express the receptor for advanced glycation end-products, but its ligands N ε -(carboxymethyl)lysine-modified proteins, methylglyoxal-modified proteins, S100B polypeptide and amyloid-β (1-40) peptide, exert no mitogenic action. Instead, oleate, one of the most common fatty acids in triglycerides, enhances platelet-derived growth factor-BB-mediated proliferation and oleate-containing 1,2-diacylglycerol formation in smooth muscle cells. This mitogenic effect of oleate depends on phospholipase D activity and is associated with an increased formation of oleate-enriched 1,2-diacylglycerol. Conclusion/interpretation. Oleate, not ligands of the receptor for advanced glycation end-products, acts as an enhancer of human smooth muscle cell proliferation. Thus, lipid abnormalities, rather than hyperglycaemia, could be a major factor promoting proliferation of smooth muscle cells in atherosclerotic lesions. [Diabetologia (2003[Diabetologia ( ) 46:1676[Diabetologia ( -1687 Keywords Atherosclerosis, diabetes, diacylglycerol, fatty acids, platelet-derived growth factor, phospholipase D, triglycerides. Atherosclerosis is accelerated by both Type I and Type 2 diabetes [1] by mechanisms that are poorly understood. Proliferation of arterial smooth muscle cells (SMCs) in lesions of atherosclerosis plays an important role in progression of early fatty streaks to fibroatheromas. We have recently reported that increased SMC proliferation in fibroatheromas occurs concomitantly with hyperglycaemia and an increased plasma triglyceride concentration in a porcine model of diabetes-accelerated atherosclerosis [2]. However, increased plasma glucose concentrations do not directly stimulate proliferation of SMCs isolated from these animals or from human subjects [2]. In this study, we investigated advanced glycation end-products (AGEs)

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“…Furthermore, RAGE null mice showed reduced arterial injury responses, whereas transgenic mice expressing DN-RAGE specifically in smooth muscle cells displayed significantly less neointimal thickening (13)(14)(15)(16). These results clearly demonstrate the in vivo role of RAGE signaling in VSMC dysfunction.Some of the in vitro effects mediated by RAGE and its ligands in VSMCs include increased oxidant stress, cell migration, proliferation, inflammatory gene expression, and extracellular matrix production (17)(18)(19)(20). RAGE-mediated signaling can activate multiple signaling pathways, including Ras-mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase, protein kinase C (PKC), and the Janus tyrosine kinases (JAKs), and transcription factors, including STAT3, AP1, and NF-B (21-26).…”

mentioning

confidence: 99%

“…Some of the in vitro effects mediated by RAGE and its ligands in VSMCs include increased oxidant stress, cell migration, proliferation, inflammatory gene expression, and extracellular matrix production (17)(18)(19)(20). RAGE-mediated signaling can activate multiple signaling pathways, including Ras-mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase, protein kinase C (PKC), and the Janus tyrosine kinases (JAKs), and transcription factors, including STAT3, AP1, and NF-B (21)(22)(23)(24)(25)(26).…”

mentioning

confidence: 99%

Key Role of Src Kinase in S100B-induced Activation of the Receptor for Advanced Glycation End Products in Vascular Smooth Muscle Cells

Reddy

Sahar

et al. 2006

Journal of Biological Chemistry

142

121

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The receptor for advanced glycation end products (RAGE) and its ligands have been implicated in the activation of oxidant stress and inflammatory pathways in vascular smooth muscle cells (VSMCs) leading to the initiation and augmentation of atherosclerosis. Here we report that non-receptor Src tyrosine kinase and the membrane protein caveolin-1 (Cav-1) play a key role in the activation of RAGE by S100B in VSMCs. S100B increased the activation of Src kinase and tyrosine phosphorylation of caveolin-1 in VSMCs. A RAGEspecific antibody blocked both these effects. An inhibitor of Src kinase, PP2, significantly blocked S100B-induced activation of Src kinase, mitogen-activated protein kinases, transcription factors NF-B and STAT3, superoxide production, tyrosine phosphorylation of Cav-1, VSMC migration, and expression of the pro-inflammatory genes monocyte chemotactic protein-1 and interleukin-6. Cholesterol depletion also inhibited S100B-induced effects indicating the requirement for intact caveolae in RAGE-specific signaling. Nucleofection of either a Src dominant negative mutant, or a Cav-1 mutant lacking the scaffolding domain, or Cav-1 short hairpin RNA significantly reduced S100B-induced inflammatory gene expression in VSMCs. Furthermore, VSMCs derived from insulin-resistant and diabetic db/db mice displayed increased RAGE expression, Src activation, and migration compared with those from control db/؉ mice. The RAGE antibody blocked enhanced migration in db/db cells. These studies demonstrate for the first time that, in VSMCs, Src kinase and Cav-1 play important roles in RAGE-mediated inflammatory gene expression and migration, key events associated with diabetic vascular complications. Vascular smooth muscle cell (VSMC)2 proliferation, migration, and inflammatory gene expression play important roles in the development of atherosclerotic lesions. Diabetic conditions have been shown to enhance these processes, which lead to accelerated atherosclerosis (1-4). Evidence shows that the accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) are key factors mediating these events (5-8). RAGE is a member of the immunoglobulin superfamily of cell-surface molecules and is expressed in many cell types, including VSMCs. It can be activated by multiple ligands such as amphoterin, ␤-amyloid peptide, and several short peptides belonging to the S100/calgranulin family, which includes S100B (9, 10). Recent studies using animal models showed that diabetes-induced accelerated atherosclerosis in apoE null mice is associated with enhanced accumulation of RAGE ligands and increased expression of RAGE itself (11, 12). The expression of RAGE as well as its ligands, including S100B, was increased in neointimal and medial cells. Administration of sRAGE could reduce neointimal thickening as well as VSMC proliferation in these animal models. Furthermore, RAGE null mice showed reduced arterial injury responses, whereas transgenic mice expressing DN-RAGE specifically in smooth muscle cells displa...

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Roles of Advanced Glycation Endoproducts(AGE) and Receptor for AGE on Vascular Smooth Muscle Cell Growth.

Cited by 22 publications

References 22 publications

Retinopathy Is Related to the Angiographically Detected Severity and Extent of Coronary Artery Disease in Patients With Type 2 Diabetes Mellitus

Retinopathy Is Related to the Angiographically Detected Severity and Extent of Coronary Artery Disease in Patients With Type 2 Diabetes Mellitus

Oleate, not ligands of the receptor for advanced glycation end-products, promotes proliferation of human arterial smooth muscle cells

Key Role of Src Kinase in S100B-induced Activation of the Receptor for Advanced Glycation End Products in Vascular Smooth Muscle Cells

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