Introduction
Formation and accumulation of AGEs
Non-enzymatic glycation process
The Maillard reaction
Key AGE precursors and their sources
Factors influencing AGE formation
Classification of AGEs
Type of AGEs | Precursors | Pathways involved | Related diseases/conditions |
---|---|---|---|
N^ε-(carboxymethyl)lysine (CML) | Glucose, Glyceraldehyde-3-phosphate | Non-enzymatic glycation; Maillard reaction | CVD, Diabetic nephropathy |
N^ε-(carboxyethyl)lysine (CEL) | Glyoxal, Methylglyoxal | Non-enzymatic glycation; Maillard reaction | CVD, Diabetic retinopathy |
Pyrraline | 3-Deoxyglucosone, Glyoxal | Non-enzymatic glycation; Maillard reaction | CVD, Alzheimer's disease |
Pentosidine | Ribose, Glucose | Non-enzymatic glycation; Maillard reaction | CVD, Osteoarthritis |
Methylglyoxal-derived hydroimidazolone (MG–H1) | Methylglyoxal | Non-enzymatic glycation; Maillard reaction | CVD, Diabetic neuropathy |
Glyoxal-derived hydroimidazolone (G–H1) | Glyoxal | Non-enzymatic glycation; Maillard reaction | CVD, Alzheimer's disease |
Argpyrimidine | Methylglyoxal, Arginine | Non-enzymatic glycation; Maillard reaction | CVD, Diabetic nephropathy |
Interaction of AGEs with cellular receptors
The receptor for AGEs (RAGE)
Other AGE-binding proteins and their roles
Receptor | Binding AGEs | Cellular functions | Signaling pathways involved | Related diseases/conditions |
---|---|---|---|---|
RAGE (Receptor for AGEs) | CML, CEL, Pentosidine, MG-H1 | Activation of pro-inflammatory responses | NF-κB, MAPK, ERK1/2, JNK, PI3K/Akt, NADPH oxidase | CVD, Diabetic nephropathy |
AGER1/OST-48 (Advanced glycation end product-specific receptor 1) | CML, Pyrraline | Suppression of inflammation, AGER/RAGE antagonist | Suppression of RAGE-mediated signaling | CVD, Diabetic retinopathy |
AGER2/SR-B1 (Advanced glycation end product-specific receptor 2) | CML, MG-H1 | Endocytosis and clearance of AGEs, Regulation of lipid metabolism | PKC, JAK/STAT, MAPK, NF-κB | CVD, Alzheimer's disease |
CD36 (Cluster of Differentiation 36) | CEL, Pentosidine | Macrophage foam cell formation, Oxidized LDL uptake | TLR4/TLR6, NF-κB, JNK, p38 MAPK, NADPH oxidase | Atherosclerosis, CVD |
LOX-1 (Lectin-like oxidized LDL receptor-1) | CML, Pyrraline | Endothelial dysfunction, Foam cell formation, Apoptosis | NF-κB, MAPK, NADPH oxidase, Caspases, FAK, Src family kinases | CVD, Diabetic retinopathy |
Cellular signaling pathways triggered by AGE–receptor interaction
Molecular mechanisms linking AGEs to vascular injury
Oxidative stress and inflammation
Endothelial dysfunction
Smooth muscle cell proliferation and migration
Extracellular matrix remodeling
Impaired angiogenesis and neovascularization
Potential therapeutic strategies targeting AGEs in CVD
Therapeutic strategy | Specific targets/compounds | Mechanism of action | Preclinical/clinical studies | Limitations/challenges |
---|---|---|---|---|
Inhibiting AGE formation and accumulation | Aminoguanidine, Pyridoxamine | Blocking the formation of AGEs by trapping reactive carbonyl species | Preclinical, limited clinical trials | Side effects, limited efficacy |
Alagebrium (ALT-711) | Breaks AGE crosslinks, reduces AGE accumulation | Preclinical, Phase II clinical trials | Safety concerns, Incomplete efficacy | |
Blocking AGE-receptor interactions | Soluble RAGE, Anti-RAGE antibodies | Competitively inhibits binding of AGEs to RAGE, preventing receptor activation | Preclinical, Phase I clinical trials | Limited efficacy, Immunogenicity |
AGER1/OST-48 overexpression | Enhances AGER1-mediated suppression of RAGE signaling | Preclinical | Challenges in gene therapy delivery | |
Targeting downstream signaling pathways | Inhibition of NF-κB, MAPK, PI3K/Akt | Reduces AGE-induced pro-inflammatory responses and oxidative stress | Preclinical | Potential off-target effects |
Inhibition of NADPH oxidase | Reduces AGE-induced reactive oxygen species (ROS) production | Preclinical | Potential off-target effects | |
Antioxidant and anti-inflammatory therapies | N-Acetylcysteine, Vitamin E, Curcumin | Scavenges free radicals and reduces inflammation, indirectly targeting AGE pathways | Preclinical, Some clinical studies | Limited efficacy, Need for specificity |