Overproduction of N.EPSILON.-(Carboxymethyl)lysine-Induced Neovascularization in Cultured Choroidal Explant of Aged Rat

Kobayashi, Shogo; Nomura, Masatoshi; Nishioka, Tatsuo; Kikuchi, Mio; Ishihara, Akina; Nagai, Ryoji; Hagino, Nobuyoshi

doi:10.1248/bpb.30.133

Cited by 16 publications

(11 citation statements)

References 35 publications

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“…To determine whether CML triggers STAT3 activation, CASMCs were exposed to CML-BSA (1 μ g.mL −1 ) (dose previously used and shown to have biological effects 38 ) for 15, 30, 60 minutes and 48 hours. After a 15-minute exposition, CML-BSA–treated cells showed a sustained 1.5-fold increase in STAT3 activation measured by immunoblots (ie, Y705-phosphorylated STAT3/total STAT3 ratio normalized to smooth muscle actin) compared with control CASMCs (n=3, P <0.05; Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

RAGE-Dependent Activation of the Oncoprotein Pim1 Plays a Critical Role in Systemic Vascular Remodeling Processes

Meloche

Paulin

Courboulin

et al. 2011

ATVB

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Objective Vascular remodeling diseases (VRD) are mainly characterized by inflammation and a vascular smooth muscle cells (VSMCs) proproliferative and anti-apoptotic phenotype. Recently, the activation of the advanced glycation endproducts receptor (RAGE) has been shown to promote VSMC proliferation and resistance to apoptosis in VRD in a signal transducer and activator of transcription (STAT)3-dependant manner. Interestingly, we previously described in both cancer and VRD that the sustainability of this proproliferative and antiapoptotic phenotype requires activation of the transcription factor NFAT (nuclear factor of activated T-cells). In cancer, NFAT activation is dependent of the oncoprotein provirus integration site for Moloney murine leukemia virus (Pim1), which is regulated by STAT3 and activated in VRD. Therefore, we hypothesized that RAGE/STAT3 activation in VSMC activates Pim1, promoting NFAT and thus VSMC proliferation and resistance to apoptosis. Methods/Results In vitro, freshly isolated human carotid VSMCs exposed to RAGE activator Nε-(carboxymethyl)lysine (CML) for 48 hours had (1) activated STAT3 (increased P-STAT3/STAT3 ratio and P-STAT3 nuclear translocation); (2) increased STAT3-dependent Pim1 expression resulting in NFATc1 activation; and (3) increased Pim1/NFAT-dependent VSMC proliferation (PCNA, Ki67) and resistance to mitochondrial-dependent apoptosis (TMRM, Annexin V, TUNEL). Similarly to RAGE inhibition (small interfering RNA [siRNA]), Pim1, STAT3 and NFATc1 inhibition (siRNA) reversed these abnormalities in human carotid VSMC. Moreover, carotid artery VSMCs isolated from Pim1 knockout mice were resistant to CML-induced VSMC proliferation and resistance to apoptosis. In vivo, RAGE inhibition decreases STAT3/Pim1/NFAT activation, reversing vascular remodeling in the rat carotid artery-injured model. Conclusion RAGE activation accounts for many features of VRD including VSMC proliferation and resistance to apoptosis by the activation of STAT3/Pim1/NFAT axis. Molecules aimed to inhibit RAGE could be of a great therapeutic interest for the treatment of VRD.

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Section: Resultsmentioning

confidence: 99%

RAGE-Dependent Activation of the Oncoprotein Pim1 Plays a Critical Role in Systemic Vascular Remodeling Processes

Meloche

Paulin

Courboulin

et al. 2011

ATVB

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“…(Handa 1998a; Rumble et al 1997) For example, CML has been shown to promote CNV formation in cultured choroidal explants from aged rats via stimulation of growth factors such as vascular endothelial growth factor ( VEGF ), tumor necrosis factor α ( TNF-α ) and PDGF-B. (Kobayashi et al 2007)…”

Section: Mechanisms Relating Hyperglycemia To Dr and Amdmentioning

confidence: 99%

Dietary hyperglycemia, glycemic index and metabolic retinal diseases

Chiu

Taylor

2011

Progress in Retinal and Eye Research

133

104

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The glycemic index (GI) indicates how fast blood glucose is raised after consuming a carbohydrate-containing food. Human metabolic studies indicate that GI is related to patho-physiological responses after meals. Compared with a low-GI meal, a high-GI meal is characterized with hyperglycemia during the early postprandial stage (0~2 h) and a compensatory hyperlipidemia associated with counter-regulatory hormone responses during late postprandial stage (4~6 h). Over the past three decades, several human health disorders have been related to GI. The strongest relationship suggests that consuming low-GI foods prevents diabetic complications. Diabetic retinopathy (DR) is a complication of diabetes. In this aspect, GI appears to be useful as a practical guideline to help diabetic people choose foods. Abundant epidemiological evidence also indicates positive associations between GI and risk for type 2 diabetes, cardiovascular disease, and more recently, age-related macular degeneration (AMD) in people without diabetes. Although data from randomized controlled intervention trials are scanty, these observations are strongly supported by evolving molecular mechanisms which explain the pathogenesis of hyperglycemia. This wide range of evidence implies that dietary hyperglycemia is etiologically related to human aging and diseases, including DR and AMD. In this context, these diseases can be considered metabolic retinal diseases. Molecular theories that explain hyperglycemic pathogenesis involve a mitochondria-associated pathway and four glycolysis-associated pathways, including advanced glycation end products formation, protein kinase C activation, polyol pathway, and hexosamine pathway. While the four glycolysis-associated pathways appear to be universal for both normoxic and hypoxic conditions, the mitochondria-associated mechanism appears to be most relevant to the hyperglycemic, normoxic pathogenesis. For diseases that affect tissues with highly active metabolism and that frequently face challenge from low oxygen tension, such as retina in which metabolism is determined by both glucose and oxygen homeostases, these theories appear to be insufficient. Several lines of evidence indicate that the retina is particularly vulnerable when hypoxia coincides with hyperglycemia. We propose a novel hyperglycemic, hypoxia-inducible factor (HIF) pathway, to complement the current theories regarding hyperglycemic pathogenesis. HIF is a transcription complex that responds to decreases in oxygen in the cellular environment. In addition to playing a significant role in the regulation of glucose metabolism, under hyperglycemia HIF has been shown to increase the expression of HIF-inducible genes, such as vascular endothelial growth factor (VEGF) leading to angiogenesis. To this extent, we suggest that HIF can also be described as a hyperglycemia-inducible factor. In summary, while management of dietary GI appears to be an effective intervention for the prevention of metabolic diseases, specifically AMD and DR, more interventional data is...

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“…6). The time-course of action of anti-TNF antibody on retinal neovascularization was faster than that of anti-VEGF antibody in the co-culture system, indicating that TNF may trigger release of VEGF from choroidal capillaries of the advanced-diabetic eyeball [33]. We have unpublished data that TNF facilitates to produce mRNA of VEGF and to release VEGF protein in choroidal explant of rat.…”

Section: Discussionmentioning

confidence: 86%

“…We have reported that anti-CML, anti-TNF and anti-VEGF antibodies significantly reduce the choroidal neovascularization in vitro in the early-diabetic rat (1-2 months after STZ administration) and the advanced-diabetic rat (ca. 7.5 months after STZ administration) [1,2,33], indicating that CML, TNF and VEGF have a concomitant role in overproduction of choroidal neovascularization of early-diabetic and advanced-diabetic rats. The present study demonstrates that anti-TNF antibody inhibited neovascularization of retinal capillaries both in single culture and in co-culture with choroidal capillaries of the same eyeball in advanced-diabetes (Table 1, Fig.…”

Section: Discussionmentioning

confidence: 96%

Nε-(Carboxymethyl)Lysine-Induced Choroidal Angiogenic Potential Facilitates Retinal Neovascularization in Advanced-Diabetic Rat In Vitro

Kobayashi

Nomura²,

Takahashi³

et al. 2008

TOPHARMJ

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N -(Carboxymethyl)lysine (CML) over-stimulates choroidal neovascularization in vitro in streptozotocin (STZ)-diabetic rat. In this study, we investigated the effects of CML-induced choroidal angiogenic potential on retinal neovascularization during the course of STZ-induced diabetes in rats. Retinal and choroidal explants were isolated from the same eyeball of early-diabetic, advanced-diabetic and age-matched normal rats. When retinal explant was co-cultured with early-diabetic choroidal explant, the number of retinal microvessels was significantly decreased. When retinal explant was co-cultured with advanced-diabetic choroidal explant, the number of retinal microvessels was significantly increased. Anti-CML antibody blocked the retinal changes caused by co-culture with both early-diabetic and advanceddiabetic choroidal explant. Antibodies against TNF and VEGF reduced the number of retinal microvessels in the coculture with advanced-diabetic choroidal explant. These results indicate that the CML-induced choroidal activity is associated with the angiogenic actions of TNF and VEGF on retinal capillaries in advanced diabetes. During the course of diabetic retinopathy, different actions on retinal neovascularization may operate.

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Overproduction of N.EPSILON.-(Carboxymethyl)lysine-Induced Neovascularization in Cultured Choroidal Explant of Aged Rat

Cited by 16 publications

References 35 publications

RAGE-Dependent Activation of the Oncoprotein Pim1 Plays a Critical Role in Systemic Vascular Remodeling Processes

RAGE-Dependent Activation of the Oncoprotein Pim1 Plays a Critical Role in Systemic Vascular Remodeling Processes

Dietary hyperglycemia, glycemic index and metabolic retinal diseases

Nε-(Carboxymethyl)Lysine-Induced Choroidal Angiogenic Potential Facilitates Retinal Neovascularization in Advanced-Diabetic Rat In Vitro

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