Fructose causes endothelial cell damage via activation of advanced glycation end products–receptor system

Abstract

Objective: Advanced glycation end products and their receptor – RAGE – in the adipose tissues contribute to metabolic derangements in fructose-fed rats. However, it remains unclear whether fructose could cause endothelial cell damage via the activation of AGE-RAGE. Methods: Intracellular advanced glycation end products were evaluated by dot blot analysis. Fructose-derived advanced glycation end products (Fruc-AGEs) were prepared by incubating bovine serum albumin with fructose for 8 weeks. Reactive oxygen species generation was measured using a fluorescent probe. Vascular cell adhesion molecule-1 gene expression was analysed by reverse transcription-polymerase chain reaction. Binding affinities of Fruc-AGEs to DNA-aptamer raised against Fruc-AGEs (Fruc-AGE-aptamer) or RAGE were measured with a quartz crystal microbalance. Results: Fructose increased the advanced glycation end product–specific fluorescence intensity in assay medium, while it stimulated intracellular formation of advanced glycation end products in human umbilical vein endothelial cells. Furthermore, 0.3 mM fructose for 4 days significantly increased reactive oxygen species generation and vascular cell adhesion molecule-1 gene expression in human umbilical vein endothelial cells. Fruc-AGE-aptamer, but not Control-aptamer, bound to Fruc-AGEs with Kd value of 5.60 × 10−6 M and dose-dependently inhibited the binding of Fruc-AGEs to RAGE. Moreover, Fruc-AGE-aptamer prevented the Fruc-AGE- and fructose-induced reactive oxygen species generation and vascular cell adhesion molecule-1 gene expression in human umbilical vein endothelial cells. Conclusion: This study suggests that fructose may elicit endothelial cell damage partly via the activation of AGE-RAGE axis.

Serum Albumin in Health and Disease: Esterase, Antioxidant, Transporting and Signaling Properties

“…Signaling pathways in RAGE activation include p21ras, MAP kinases, Rho GTPases, c-Jun N-terminal kinase (JNK) and JAK/STAT, which lead to the migration of transcription factors into the nucleus and the expression of genes that regulate chemotaxis, cell activation and proliferation ( Figure 5 ) [ 132 ]. NF-κB, NFAT, STAT, AP-1, ERK1/2 and CREB-TF (CREB, cAMP response element-binding protein) bind to their specific promoters for the transcription of genes encoding pro-inflammatory cytokines (e.g., IL-1, IL-2 and IL-4), proapoptotic proteins (e.g., p53-Bax, which initiates the caspase cascade), and surface proteins such as EC adhesion molecules [ 142 , 143 , 144 ]. RAGEs are constitutively expressed in many tissues, while RAGE hyperactivation induces stimulation of the PI3K–PKB–IKK pathway, resulting in NF-κB binding to RAGE promoters and autoamplification of expression ( Figure 5 ) [ 132 ].…”

Determination of the most potent precursors of advanced glycation end products in some high‐sugar containing traditional foods using high‐performance liquid chromatography

“…As seen, increasing MGO levels affect the formation of dietary AGEs levels. A significant correlation was reported between dietary AGE levels and Alzheimer's disease, aging-related disorders, and cardiovascular disease (Sotokawauchi, Matsui, Higashimoto, & Yamagishi, 2019). Consuming α-DCs in the diet leads to the formation of final AGEs with the presence of protein in the human body (Sharma et al, 2015).…”

Integrative Role of Albumin: Evolutionary, Biochemical and Pathophysiological Aspects

“…Signaling pathways during the activation of RAGE include p21ras, MAP kinases, Rho GTPases, N-terminal kinase Jun (JNK) and JAK/STAT, which lead to the migration of transcription factors into the nucleus and the expression of genes which regulate chemotaxis, cell activation and proliferation [ 58 ]. NF-κB, NFAT, STAT, AP-1, ERK1/2 and the protein binding the cAMP-sensitive element bind to their specific promoters for transcription of genes encoding pro-inflammatory cytokines (for example, IL-1, IL-2 and IL-4), pro-apoptotic proteins (for example, p53-Bax, which initiates the cascade of caspases) and surface proteins, such as endothelial cell adhesion molecules [ 68 – 70 ]. RAGE is constitutively expressed in many tissues, whereas RAGE hyperactivation causes stimulation of the PI3K–PKB–IKK pathway, which leads to binding of NF-κB on the RAGE promoter and autoamplification of expression [ 58 ].…”