Advanced glycation, endothelial dysfunction, and the LDL paradox: Is it truly the 'bad' lipid?

Glycation, a non-enzymatic reaction between reducing sugars and biomolecules, generates advanced glycation end products (AGEs) that accumulate with ageing, diabetes, and metabolic stress. Beyond their well-known role in food chemistry, AGEs exert profound biological effects by modifying long-lived proteins, nucleic acids, and lipids, thereby altering structural integrity and cellular signalling. Emerging evidence implicates AGEs in endothelial dysfunction, a central event in cardiovascular pathology, and in the modification of low-density lipoprotein (LDL), traditionally considered the "bad cholesterol". AGEs promote vascular injury via structural remodelling of the extracellular matrix, eNOS uncoupling, and activation of the AGE-RAGE axis, triggering MAPK- and NF-κB-mediated proinflammatory cascades. These changes amplify oxidative stress, adhesion molecule expression, and endothelin-1 activity, accelerating vascular inflammation and atherosclerosis. Glycation of apolipoprotein B impairs LDL receptor recognition, prolonging LDL residence in circulation and enhancing susceptibility to further oxidative modifications, thereby potentiating foam cell formation. LDL cholesterol also exerts a reparative role by stimulating CD34+ progenitor cell expansion, which supports endothelial repair. The balance between endothelial damage and progenitor-driven repair determines whether LDLc acts predominantly as atherogenic or protective. The interplay of AGEs, endothelial dysfunction, and LDL modification underscores a dualistic phenomenon, while glycated and oxidized LDL drive vascular injury, native LDL may facilitate vascular repair through progenitor cell mobilization. This paradox reframes LDL not as an inherently "bad lipid" but as a context-dependent regulator of vascular health. Targeting AGE-RAGE signalling and preserving LDL's reparative potential may offer novel therapeutic avenues in diabetes- and age-related cardiovascular disease.