Glycation of low-density lipoproteins by methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-laden cells.
OBJECTIVE
Previous studies have implicated the glycoxidative modification of low-density lipoprotein (LDL) by glucose and aldehydes (apparently comprising both glycation and oxidation), as a causative factor in the elevated levels of atherosclerosis observed in diabetic patients. Such LDL modification can result in unregulated cellular accumulation of lipids. In previous studies we have characterized the formation of glycated, but nonoxidized, LDL by glucose and aldehydes; in this study we examine whether glycation of LDL, in the absence of oxidation, gives rise to lipid accumulation in arterial wall cell types.


METHODS
Glycated LDLs were incubated with macrophage, smooth muscle, or endothelial cells. Lipid loading was assessed by HPLC analysis of cholesterol and individual esters. Oxidation was assessed by cholesterol ester loss and 7-ketocholesterol formation. Cell viability was assessed by lactate dehydrogenase release and cell protein levels.


RESULTS
Glycation of LDL by glycolaldehyde and methylglyoxal, but not glucose (in either the presence or absence of copper ions), resulted in cholesterol and cholesterol ester accumulation in macrophage cells, but not smooth muscle or endothelial cells. The extent of lipid accumulation depends on the degree of glycation, with increasing aldehyde concentration or incubation time, giving rise to greater extents of particle modification and lipid accumulation. Modification of lysine residues appears to be a key determinant of cellular uptake.


CONCLUSIONS
These results are consistent with LDL glycation, in the absence of oxidation, being sufficient for rapid lipid accumulation by macrophage cells. Aldehyde-mediated "carbonyl-stress" may therefore facilitate the formation of lipid-laden (foam) cells in the artery wall.
Brown
B E
BE
Free Radical Group, The Heart Research Institute, 145 Missenden Road, Camperdown, Sydney 2050, Australia.
Dean
R T
RT
Davies
M J
MJ
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000737:chemistry*; D000818:Animals; D017127:Glycation End Products, Advanced; D006801:Humans; D007202:Indicators and Reagents; D008074:Lipoproteins / Q000097:blood*; D008077:Lipoproteins, LDL / Q000138:chemical synthesis*; D011765:Pyruvaldehyde / Q000737:chemistry*; D051381:Rats; D000093844:Glycated Proteins
D000079:Acetaldehyde; D017127:Glycation End Products, Advanced; D007202:Indicators and Reagents; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011765:Pyruvaldehyde; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins; C010972:glycolaldehyde