Mechanisms of inhibitory activity of the aldose reductase inhibitor, epalrestat, on high glucose-mediated endothelial injury

Okayama, Naotsuka; Omi, Hitoshi; Okouchi, Masahiro; Imaeda, Kazuo; Kato, Takashi; Akao, Masaya; Imai, Seiji; Shimizu, Manabu; Fukutomi, Tatsuya; Itoh, Makoto

doi:10.1016/s1056-8727(02)00178-2

Cited by 30 publications

(26 citation statements)

References 22 publications

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“…In contrast, diabetes in mice caused a modest elevation of the retinal sorbitol pathway activity. Numerous findings indicate that increased activity of the first enzyme of the sorbitol pathway, AR, contributes to increased vascular permeability [26,27] and leucocyte adhesion to the endothelial wall [28,29], accelerated pericyte and endothelial cell apoptosis [4,30] and formation of pericyte ghosts and acellular capillaries [2,4], as well as VEGF overexpression [3,14,31] and neovascularisation [12,27] associated with diabetic and diabetes-like retinopathy. Furthermore, increased AR activity is also involved in the accelerated apoptosis of inner retinal neurons and increased expression of glial fibrillary acidic protein (GFAP) in Muller glial cells [32].…”

Section: Discussionmentioning

confidence: 99%

Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models

et al. 2006

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Aims/hypothesis Recently, various transgenic and knockout mouse models have become available for studying the pathogenesis of diabetic retinopathy. At the same time, diabetes-induced retinal changes in the wild-type mice remain poorly characterised. The present study compared retinal biochemical changes in rats and mice with similar (6-week) durations of streptozotocin-induced diabetes. Materials and methods The experiments were performed on Wistar rats and C57Bl6/J mice. Retinal glucose, sorbitol, fructose, lactate, pyruvate, glutamate, α-ketoglutarate and ammonia were measured spectrofluorometrically by enzymatic methods. Vascular endothelial growth factor (VEGF) protein was assessed by ELISA, and poly(ADP-ribosyl)ation by immunohistochemistry and western blot analysis. Free mitochondrial and cytosolic NAD + /NADH ratios were calculated from the glutamate and lactate dehydrogenase systems. Results Retinal glucose concentrations were similarly increased in diabetic rats and mice, vs controls. Diabetic rats manifested ∼26-and 5-fold accumulation of retinal sorbitol and fructose, respectively, whereas elevation of both metabolites in diabetic mice was quite modest. Correspondingly, diabetic rats had (1) increased retinal malondialdehyde plus 4-hydroxyalkenal concentrations, (2) reduced superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase and glutathione transferase activities, (3) slightly increased poly(ADP-ribose) immunoreactivity and poly(ADP-ribosyl)ated protein abundance, and (4) VEGF protein overexpression. Diabetic mice lacked these changes. SOD activity was 21-fold higher in murine than in rat retinas (the difference increased to 54-fold under diabetic conditions), whereas other antioxidative enzyme activities were 3-to 10-fold lower. With the exception of catalase, the key antioxidant defence enzyme activities were increased, rather than reduced, in diabetic mice. Diabetic rats had decreased free mitochondrial and cytosolic NAD + / NADH ratios, consistent with retinal hypoxia, whereas both ratios remained in the normal range in diabetic mice. Conclusions/interpretation Mice with short-term streptozotocin-induced diabetes lack many biochemical changes that are clearly manifest in the retina of streptozotocin-diabetic rats. This should be considered when selecting animal models for studying early retinal pathology associated with diabetes.

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Section: Discussionmentioning

confidence: 99%

Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models

et al. 2006

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“…The "high-glucose concentration" is a concentration of glucose that causes endothelial injury (21). Sarpogrelate was used at concentrations that inhibit aggregation of human and rat platelets (22), and aspirin was used at a concentration that inhibits aggregation of human platelets (23).…”

Section: Cell Culture and Experimental Protocol In Vitromentioning

confidence: 99%

Serotonin Potentiates High-Glucose^|^ndash;Induced Endothelial Injury: the Role of Serotonin and 5-HT2A Receptors in Promoting Thrombosis in Diabetes

Yamada¹,

Niki²,

Nagai³

et al. 2012

J Pharmacol Sci

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Abstract. To clarify the involvement of 5-hydroxytryptamine (5-HT) in promotion of thrombogenesis in diabetes, we examined the inhibitory effect of sarpogrelate, a 5-HT 2A receptor antagonist, on thrombus formation in diabetic rats. In streptozotocin-induced diabetic rats, polyethylene tubeinduced thrombus formation was enhanced compared with that in normal rats. The thrombogenesis was inhibited by sarpogrelate; cilostazol, a PDE3 inhibitor; and aspirin, a COX inhibitor, by 75.8%, 42.3%, and 34.3%, respectively. The inhibition by sarpogrelate was more pronounced in diabetic rats than normal ones. High glucose and 5-HT increased the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) and combination of both high glucose and 5-HT further potentiated the effect. Sarpogrelate but not aspirin inhibited the increase in VCAM-1 expression induced by high glucose and 5-HT. These findings suggest that 5-HT mediates the enhanced thrombogenesis in diabetes and suggests that a 5-HT 2A receptor antagonist may have novel therapeutic potential for the treatment of diabetic complications.

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“…9,10) Incubation of human umbilical vein endothelial cells (HUVEC) in culture media containing high glucose enhances the expression of cell surface adhesion molecules through a process that involves nuclear factor-kB (NF-kB), 11) protein kinase C, [12][13][14] and poly ADP ribose polymerase, 15) although the precise mechanism remains to be elucidated. In a previous report, 16) we demonstrated that glycated human serum albumin enhanced E-selectin expression on HUVEC by NF-kB and activator protein-1 (AP-1) via NADPH oxidase activation.…”

Section: )mentioning

confidence: 99%

“…8) Serum concentrations of soluble adhesion molecules such as soluble endothelial leukocyte adhesion molecule (ELAM-1, E-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) are related to the degree of insulin resistance and hyperglycemia in patients with type 2 diabetes. 9,10) Incubation of human umbilical vein endothelial cells (HUVEC) in culture media containing high glucose enhances the expression of cell surface adhesion molecules through a process that involves nuclear factor-kB (NF-kB), 11) protein kinase C, [12][13][14] and poly ADP ribose polymerase, 15) although the precise mechanism remains to be elucidated. In a previous report, 16) we demonstrated that glycated human serum albumin enhanced E-selectin expression on HUVEC by NF-kB and activator protein-1 (AP-1) via NADPH oxidase activation.…”

Section: Protein O-glcnacylation Is Catalyzed By O-glcnac Transferasementioning

confidence: 99%

Protein O-N-Acetylglucosaminylation Modulates Promoter Activities of Cyclic AMP Response Element and Activator Protein 1 and Enhances E-Selectin Expression on HuH-7 Human Hepatoma Cells

Azuma

Miura

Higai

et al. 2007

Biological & Pharmaceutical Bulletin

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A variety of cytoplasmic and nuclear proteins, including transcription factors, cytoskeletal proteins, nuclear pore proteins, and oncogene products, can be modified on serine and threonine residues by O-linked b-N-acetylglucosamine (OGlcNAc).1,2) This post-translational modification is dynamic and inducible and occurs at sites similar and adjacent to phosphorylation sites that are thought to influence protein functions. Therefore, regulation by O-GlcNAcylation is thought to compete with regulation by phosphorylation/dephosphorylation. Furthermore, nuclear transport of proteins is reported to be regulated by the balance of O-GlcNAcylation and phosphorylation.3) These findings suggest that protein O-GlcNAcylation plays an important role in signal transduction and cellular function. 4,5) Protein O-GlcNAcylation is catalyzed by O-GlcNAc transferase (OGT) using uridine diphosphate (UDP)-GlcNAc as a donor substrate. The transferred O-GlcNAc is reversed by OGlcNAc hexosaminidase (O-GlcNAcase).6) UDP-GlcNAc is generated intracellularly from glucose by the hexosamine biosynthesis pathway, wherein glutamine fructose-6-phosphate amidotransferase (GFAT) is a rate-limiting enzyme. Therefore, protein O-GlcNAcylation is regulated by the cellular levels of OGT, O-GlcNAcase, GFAT, and glucose. 7)Hyperglycemia enhances the levels of UDP-GlcNAc and protein O-GlcNAcylation, and perturbations in the regulation of protein O-GlcNAcylation have been implicated in diabetes mellitus, cancer, and neurodegenerative diseases.8) Serum concentrations of soluble adhesion molecules such as soluble endothelial leukocyte adhesion molecule (ELAM-1, E-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) are related to the degree of insulin resistance and hyperglycemia in patients with type 2 diabetes.9,10) Incubation of human umbilical vein endothelial cells (HUVEC) in culture media containing high glucose enhances the expression of cell surface adhesion molecules through a process that involves nuclear factor-kB (NF-kB), 11) protein kinase C, [12][13][14] and poly ADP ribose polymerase, 15) although the precise mechanism remains to be elucidated. In a previous report, 16) we demonstrated that glycated human serum albumin enhanced E-selectin expression on HUVEC by NF-kB and activator protein-1 (AP-1) via NADPH oxidase activation. In type 2 diabetes and the metabolic syndrome, hepatocellular inflammation by hepatic steatosis was also associated with the development of local and systemic insulin resistance. 17,18) It has been established that pro-inflammatory cytokines such as interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) enhance the expression of these adhesion molecules, although there are different patterns of expression among them.19) The organization of the cytokine-inducible element in the E-selectin expression promotor requires NFkB, activating transcription factor-2 (ATF-2), and high mobility group protein (HMG) I(Y) for induction and these interact as a unit with the basal transcr...

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Mechanisms of inhibitory activity of the aldose reductase inhibitor, epalrestat, on high glucose-mediated endothelial injury

Cited by 30 publications

References 22 publications

Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models

Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models

Serotonin Potentiates High-Glucose^|^ndash;Induced Endothelial Injury: the Role of Serotonin and 5-HT2A Receptors in Promoting Thrombosis in Diabetes

Protein O-N-Acetylglucosaminylation Modulates Promoter Activities of Cyclic AMP Response Element and Activator Protein 1 and Enhances E-Selectin Expression on HuH-7 Human Hepatoma Cells

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