Hydrazine compounds inhibit glycation of low-density lipoproteins and prevent the in vitro formation of model foam cells from glycolaldehyde-modified low-density lipoproteins.
OBJECTIVE
Previous studies have shown that glycation of LDL by methylglyoxal and glycolaldehyde, in the absence of significant oxidation, results in lipid accumulation in macrophage cells. Such 'foam cells' are a hallmark of atherosclerosis. In this study we examined whether LDL glycation by methylglyoxal or glycolaldehyde, and subsequent lipid loading of cells, can be inhibited by agents that scavenge reactive carbonyls. Such compounds may have therapeutic potential in diabetes-associated atherosclerosis.


METHODS
LDL was glycated with methylglyoxal or glycolaldehyde in the absence or presence of metformin, aminoguanidine, Girard's reagents P and T, or hydralazine. LDL modification was characterised by changes in mobility (agarose gel electrophoresis), cross-linking (SDS-PAGE) and loss of amino acid residues (HPLC). Accumulation of cholesterol and cholesteryl esters in murine macrophages was assessed by HPLC.


RESULTS
Inhibition of LDL glycation was detected with equimolar or greater concentrations of the scavengers over the reactive carbonyl. This inhibition was structure-dependent and accompanied by a modulation of cholesterol and cholesteryl ester accumulation. With aminoguanidine, Girard's reagent P and hydralazine, cellular sterol levels returned to control levels despite incomplete inhibition of LDL modification.


CONCLUSIONS
Inhibition of LDL glycation by interception of the reactive aldehydes that induce LDL modification prevents lipid loading and model foam cell formation in murine macrophage cells. Carbonyl-scavenging reagents, such as hydrazines, may therefore help inhibit LDL glycation in vivo and prevent diabetes-induced atherosclerosis.
Brown
B E
BE
Free Radical Group, The Heart Research Institute, 145 Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
Mahroof
F M
FM
Cook
N L
NL
van Reyk
D M
DM
Davies
M J
MJ
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D015394:Molecular Structure
D006834:Hydrazines; D008077:Lipoproteins, LDL; D000079:Acetaldehyde; C010972:glycolaldehyde