Hydrazine compounds inhibit glycation of low-density lipoproteins and prevent the in vitro formation of model foam cells from glycolaldehyde-modified low-density lipoproteins

Abstract

Aims/hypothesis: 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 diabetesassociated 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.

Metformin Restores Intermediate-Conductance Calcium-Activated K+Channel– and Small-Conductance Calcium-Activated K+Channel–Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery

“…Metformin is a guanidine compound that is structurally related to aminoguanidine, and has been reported to have a potential effect on the inhibition of glycation reactions (Tanaka et al, 1997;Ruggiero-Lopez et al, 1999;Kiho et al, 2005;Brown et al, 2006). Metformin therapy reduced the atherogenic AGE molecules in the serum of women with polycystic ovary syndrome (Diamanti-Kandarakis et al, 2007).…”

Effective and rapid electrochemical detection of hydrazine by nanoporous gold

“…In addition, direct liquid fuel cells based on hydrazine are also developed due to its high energy density and its high reactive property [2]. Hydrazine is also applied as intermediate in chemical industry to synthesize pesticides and herbicides as well as the production of anti-tuberculosis and anti-diabetes medicines [3][4][5]. On the other hand, hydrazine is quite toxic, which can cause liver and kidney damages when people explored to the air containing 10 ppb hydrazine [6,7].…”

The effect of natural dicarbonyls on activity of antioxidant enzymes in vitro and in vivo

“…In our view point, significantly higher increase in erythrocyte Cu,Zn SOD observed in blood of diabetic patients treated with metformin may be well explained by increased utilization of a potential SOD inhibitor, methylglyoxal [31]. Indeed, some studies provided experimental evidence that some hydrazine com pounds (to which metformin belongs) may protect various proteins and LDL against methylglyoxal mod ification [32,33].…”