Abstract:
Aims/hypothesis: Previous studies have shown
that glycation of LDL by methyl glyoxal 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. Materials and 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/
interpretation: 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.
