Effects of cross-link breakers, glycation inhibitors and insulin sensitisers on HDL function and the non-enzymatic glycation of apolipoprotein A-I.
OBJECTIVE
Hyperglycaemia, a key feature of diabetes, is associated with non-enzymatic glycation of plasma proteins. We have shown previously that the reactive alpha-oxoaldehyde, methylglyoxal, non-enzymatically glycates apolipoprotein (Apo)A-I, the main apolipoprotein of HDL, and prevents it from activating lecithin:cholesterol acyltransferase (LCAT), the enzyme that generates almost all of the cholesteryl esters in plasma. This study investigates whether the glycation inhibitors aminoguanidine and pyridoxamine, the insulin sensitiser metformin and the cross-link breaker alagebrium can inhibit and/or reverse the methylglyoxal-mediated glycation of ApoA-I and whether these changes can preserve or restore the ability of ApoA-I to activate LCAT.


METHODS
Inhibition of ApoA-I glycation was assessed by incubating aminoguanidine, pyridoxamine, metformin and alagebrium with mixtures of methylglyoxal and discoidal reconstituted HDL (rHDL) containing phosphatidylcholine and ApoA-I, ([A-I]rHDL). Glycation was assessed as the modification of ApoA-I arginine, lysine and tryptophan residues, and by the extent of ApoA-I cross-linking. The reversal of ApoA-I glycation was investigated by pre-incubating discoidal (A-I)rHDL with methylglyoxal, then incubating the modified rHDL with aminoguanidine, pyridoxamine or alagebrium.


RESULTS
Aminoguanidine, pyridoxamine, metformin and alagebrium all decreased the methylglyoxal-mediated glycation of the ApoA-I in discoidal rHDL and conserved the ability of the particles to act as substrates for LCAT. However, neither aminoguanidine, pyridoxamine nor alagebrium could reverse the glycation of ApoA-I or restore its ability to activate LCAT.


CONCLUSIONS
Glycation inhibitors, insulin sensitisers and cross-link breakers are important for preserving normal HDL function in diabetes.
Nobécourt
E
E
Lipid Research Group, The Heart Research Institute, 145 Missenden Road, Camperdown, Sydney, NSW 2050, Australia.
Zeng
J
J
Davies
M J
MJ
Brown
B E
BE
Yadav
S
S
Barter
P J
PJ
Rye
K-A
KA
D016632:Apolipoprotein A-I / Q000097:blood* / Q000187:drug effects; D001120:Arginine / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D006031:Glycosylation; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood / Q000187:drug effects; D008239:Lysine / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood; D011733:Pyridoxamine / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014364:Tryptophan / Q000378:metabolism
C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D003432:Cross-Linking Reagents; D006146:Guanidines; D008075:Lipoproteins, HDL; D013844:Thiazoles; D011733:Pyridoxamine; D011765:Pyruvaldehyde; D014364:Tryptophan; D008687:Metformin; D001120:Arginine; C406794:alagebrium; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008239:Lysine; C004479:pimagedine