Stimulatory effects of advanced glycation endproducts (AGEs) on fibronectin matrix assembly

Abstract

Advanced glycation endproducts (AGEs) are a heterogeneous group of compounds that form via non-enzymatic glycation of proteins throughout our lifespan and at a higher rate in certain chronic diseases such as diabetes. AGEs contribute to the progression of fibrosis, in part by stimulating cellular pathways that affect gene expression. Long-lived ECM proteins are targets for non-enzymatic glycation but the question of whether the AGE-modified ECM leads to excess ECM accumulation and fibrosis remains unanswered. In this study, cellular changes due to AGE accretion in the ECM were investigated. Non-enzymatic glycation of proteins in a decellularized fibroblast ECM was achieved by incubating the ECM in a solution of methylglyoxal (MGO). Mass spectrometry of fibronectin (FN) isolated from the glycated matrix identified twenty-eight previously unidentified MGO-derived AGE modification sites including functional sites such as the RGD integrin-binding sequence. Mesangial cells grown on the glycated, decellularized matrix assembled increased amounts of FN matrix. Soluble AGE-modified bovine serum albumin (BSA) also stimulated FN matrix assembly and this effect was reduced by function-blocking antibodies against the receptor for AGE (RAGE). These results indicate that cells respond to AGEs by increasing matrix assembly and that RAGE is involved in this response. This raises the possibility that the accumulation of ECM during the progression of fibrosis may be enhanced by cell interactions with AGEs on a glycated ECM.

Redox Signaling and Advanced Glycation Endproducts (AGEs) in Diet-Related Diseases

“…Therefore, AGE-induced crosslinking of fibronectin promotes matrix accumulation by increasing the stiffness of collagen. In addition, the AGE-mediated crosslinking of collagen IV and laminin promotes the stiffening of the basal lamina matrix [166,172].…”

Time‐dependent changes in extra‐domain A‐fibronectin concentration and relative amounts of fibronectin‐fibrin complexes in plasma of patients with peripheral arterial disease after endovascular revascularisation

“…EDA‐FN with its known pro‐inflammatory and pro‐thrombotic activities is secreted at high concentrations into the plasma of PAD patients during the first and second stages after revascularisation (Table ) and with disease progression and restenosis occurrence (Figure B). Some changes in EDA‐FN concentration have also been found in the plasma of patients with advanced coronary artery disease, thrombosis, and diabetes …”

“…Diabetes and ulceration were reported to be associated with increased deposition of FN in ECM and linked with the occurrence of FN modified by glycation and/or hypoxia. Such structural modification may cause its reduced functionality . The lack of EDA‐FN as well as a low concentration of functional EDA‐FN may lead to exacerbation of vascular damage and delay in normal tissue remodelling .…”

“…Some changes in EDA-FN concentration have also been found in the plasma of patients with advanced coronary artery disease, 27 thrombosis, 15,38 and diabetes. [39][40][41] Diabetes and ulceration were reported to be associated with increased deposition of FN in ECM and linked with the occurrence of FN modified by glycation and/or hypoxia. Such structural modification may cause its reduced functionality.…”

“…Such structural modification may cause its reduced functionality. 39,[41][42][43][44] The lack of EDA-FN as well as a low concentration of functional EDA-FN may lead to exacerbation of vascular damage and delay in normal tissue remodelling. 45 Thus, in our opinion, the low mean values of plasma EDA-FN concentration in the groups of PAD patients with comorbid diabetes in the period of 1 to 3 months after revascularisation (3.9 AE 2.5 mg/L) ( Figure 2B) and PAD complicated by ulceration within 3 to 6 months after revascularisation (2.4 AE 0.5 mg/L) ( Figure 3B), compared with those of non-diabetic (7.4 AE 3.5 mg/L; P < .02) and ulcerfree (4.1 AE 3.7 mg/L; P < .009) groups, might be related to its insufficient local production by impaired endothelium and other cells involved in arterial remodelling and its deposition in the ECM.…”