RAGE-dependent activation of gene expression of superoxide dismutase and vanins by AGE-rich extracts in mice cardiac tissue and murine cardiac fibroblasts

Abstract

Advanced glycation end products (AGEs) are stable compounds formed from initial Maillard reaction products. They are considered as markers for ageing and often associated with age-related, degenerative diseases. Bread crust represents an established model for nutritional compounds rich in AGEs and is able to induce antioxidative defense genes such as superoxide dismutases and vanins in cardiac cells. The aim of this study was to investigate to what extend the receptor for AGEs (RAGE) contributes to this response. Signal transduction in response to bread crust extract was analysed in cardiac fibroblasts derived from C57/B6-NCrl (RAGE +/+) and the corresponding RAGE-knock out C57/B6-NCrl mouse strain (RAGE -/-). Activation of superoxide dismutases in animals was then analysed upon bread crust feeding in these two mice strains. Cardiac fibroblasts from RAGE -/- mice did not express RAGE, but the expression of AGER-1 and AGER-3 was up-regulated, whereas the expression of SR-B1 was down-regulated. RAGE -/- cells were less sensitive to BCE in terms of MAP-kinase phosphorylation and NF-κB reporter gene activation. Bread crust extract induced mRNA levels of MnSOD and Vnn-1 were also reduced in RAGE -/- cells, whereas Vnn-3 mRNA accumulation seemed to be RAGE receptor independent. In bread crust feeding experiments, RAGE -/- mice did not exhibit an activation of MnSOD-mRNA and -protein accumulation as observed for the RAGE +/+ animals. In conclusion, RAGE was clearly a major factor for the induction of antioxidant defense signals derived from bread crust in cardiac fibroblast and mice. Nevertheless higher doses of bread crust extract could overcome the RAGE dependency in cell cultures, indicating that additional mechanisms are involved in BCE-mediated activation of SOD and vanin expression.

Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade

“…ROS production within cells can be upregulated when exposed to specific factors, such as high glucose levels or AGEs [ 5 , 11 ]. Increased ROS production, as well as increased RAGE signaling triggered by the presence of AGEs, can result in increased SOD expression [ 5 , 12 , 20 ]. SODs convert superoxides into hydrogen peroxide (H 2 O 2 ), which can be further reduced by peroxidases to rid the body of reactive oxygen stressors [ 21 , 80 ].…”

“…Increased PKC, ERK1/2, and ROS production can also promote ECM remodeling, denoted by increased collagen synthesis and MMP activity [ 5 , 15 , 16 , 17 , 18 ]. Increased superoxides generation AGE/RAGE signaling can be reduced by increased expression of SODs converting superoxides into hydrogen peroxide [ 19 , 20 , 21 ]. In addition to ROS production, the AGE/RAGE signaling cascade can elicit myofibroblast differentiation, marked by increased α-SMA expression, which has been shown to increase collagen matrix contraction [ 22 , 23 , 24 ].…”

[Retracted] 5‐Aminolevulinic Acid‐Based Photodynamic Therapy Pretreatment Mitigates Ultraviolet A‐Induced Oxidative Photodamage

“…It has been reported that bread crust extract could activate SOD through the receptor for advanced glycation end products (AGEs). But high doses of bread crust extract are independent of AGE receptors, indicating that additional mechanisms are involved in the activation of SOD [ 52 ]. In our experiments, sublethal doses of ALA-PDT induced an antioxidant response by activation of SOD1 and SOD2, but the specific activation mechanism of SODs remained to be further studied.…”

Evaluation of the Availability and Antioxidant Capacity of Maillard Compounds Present in Bread Crust: Studies in Caco-2 Cells

“…On the other hand, the consumption of the glycose-lysine MRP in the diet did not affect the hepatic antioxidant defence of Wistar rats, while some positive modifications (e.g., an increase in glutathione peroxidase) were detected in muscle (29%) and serum (400%), pointing to an improved antioxidant capacity after the consumption of those model MRP [ 48 ]. On the other hand, as previously mentioned, the work by Leuner et al [ 14 ] in mice and their cardiac fibroblasts demonstrated that bread crust feeding induced the activation of the antioxidant defence by the increase in the gene expression of superoxide dismutase. The authors suggested that bread crust might be a promising tool as a preconditioning agent to protect cardiac cells against ischemia–reperfusion damage.…”

“…A recent study developed in mice and cardiac fibroblasts derived from them have established that RAGEs (the best-characterized AGE-receptor) are activated by dietary bread crust-derived AGEs. Next, the induction of antioxidant defence through the activation of the gene expression of superoxide dismutase takes place, suggesting that bread crust might be useful as a preconditioning agent to protect cardiac cells against ischemia–reperfusion damage [ 14 ].…”