Advanced Glycation End Products Enhance Expression of Pro-apoptotic Genes and Stimulate Fibroblast Apoptosis through Cytoplasmic and Mitochondrial Pathways

Abstract

Both aging and diabetes are characterized by the formation of advanced glycation end products (AGEs). Both exhibit other similarities including deficits in wound healing that are associated with higher rates of fibroblast apoptosis. In order to investigate a potential mechanism for enhanced fibroblast apoptosis in diabetes and aged individuals, experiments were carried out to determine whether the predominant advanced glycation end product in skin, N-⑀-(carboxymethyl) lysine (CML)-collagen, could induce fibroblast apoptosis. In vivo experiments established that CML-collagen but not unmodified collagen induced fibroblast apoptosis and that apoptosis was dependent upon caspase-3, -8, and -9 activity. In vitro experiments demonstrated that CMLcollagen but not control collagen induced a time-and dose-dependent increase in fibroblast apoptosis. By use of blocking antibodies, apoptosis was shown to be mediated through receptor for AGE signaling. AGE-induced apoptosis was largely dependent on the effector caspase, caspase-3, which was activated through both cytoplasmic (caspase-8-dependent) and mitochondrial (caspase-9) pathways. CML-collagen had a global effect of enhancing mRNA levels of pro-apoptotic genes that included several classes of molecules including ligands, receptors, adaptor molecules, mitochondrial proteins, and others. However, the pattern of expression was not identical to the pattern of apoptotic genes induced by tumor necrosis factor ␣.

Investigating variables and mechanisms that influence protein integrity in low water content amorphous carbohydrate matrices

“…1 Animal species (in addition to others) have, therefore, developed protective mechanisms to either prevent or reverse these damaging reactions, or alternatively to remove and degrade such modified proteins. Such modifications are also observed in proteins in vitro, however, additional degradations and rearrangements are also often observed in solution including hydrolysis (particularly at Asp-Pro motifs), disulphide cross-linking and diketopiperazine formation, 2 all of which can result in the damaging loss of protein integrity, decreased or abolished bioactivity, and increased immunogenicity.…”

Chinese Purple Yam (<i>Dioscorea alata</i> L.) Extracts Inhibit Diabetes-Related Enzymes and Protect HepG2 Cells Against Oxidative Stress and Insulin Resistance Induced by FFA

“…However, in diabetic patients, increased glycation resulted from hyperglycaemia was observed with AGEs formation up to four times (Alikhani et al, 2005). Therefore, it's urgent to search for anti-glycation agents from natural sources to offer promising therapeutic approaches for T2D.…”

Collagen expression in fibroblasts with a novel LMNA mutation

“…The characteristic change of aged extracellular matrix is the accumulation of collagen glycoxidation generated by the so-called Maillard reaction. These advanced glycation endproducts (AGEs) are seen in aged skin from a wide variety of mammalian species [35], and has been implicated in the apoptosis of dermal fibroblasts [36]. Our initial investigation of collagen protein production therefore needs to be expanded to include the examination of these biomarkers of aging.…”