Aminoguanidine and metformin prevent the reduced rate of HDL-mediated cell cholesterol efflux induced by formation of advanced glycation end products.
OBJECTIVE
The mechanisms whereby advanced glycation end products (AGE) contribute to atherogenesis in diabetes mellitus are not fully understood. In this study we analyzed in vitro the influence of advanced glycated albumin (AGE-albumin) as well as the role of the AGE inhibitors--aminoguanidine (AMG) and metformin (MF)--on the cell cholesterol efflux.


METHODS
HDL3 and albumin-mediated cholesterol efflux was measured in mouse peritoneal macrophages and in SR-BI transfected cells that had been treated along time with dicarbonyl sugars or AGE-albumin, both in the presence or in the absence of AMG and MF. 125I-HDL3 cell binding and 125I-AGE-albumin cell degradation were measured. Carboxymethyllysine (CML) formation and SR-BI expressions were determined by immunoblot.


RESULTS
AGE-albumin efficiently trapped cell cholesterol but impaired the HDL-mediated cell cholesterol efflux by decreasing HDL binding to the cell surface and inducing intracellular glycoxidation, without interfering with the SR-BI expression. Cell treatment with dicarbonyl sugars also disrupted the HDL-mediated cell cholesterol efflux, but this was prevented by AMG and MF that reduced CML formation.


CONCLUSIONS
By adversely impairing the HDL-mediated cell cholesterol removal rate, AGE-albumin and cell glycoxidation could facilitate the development of premature atherosclerosis in diabetes mellitus (DM) and in other diseases associated with carbonyl and oxidative stress like in chronic uremia. Thus, drugs that prevent AGE formation may be useful to correct disturbances in cell cholesterol transport.
Machado
Adriana P
AP
Lipids Laboratory (LIM-10), University of São Paulo Medical School, Av. Dr. Arnaldo 455, Room 3317, CEP 01246-000 São Paulo, Brazil.
Pinto
Raphael S
RS
Moysés
Zenaide P
ZP
Nakandakare
Edna R
ER
Quintão
Eder C R
EC
Passarelli
Marisa
M
D000418:Albumins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006146:Guanidines / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D008687:Metformin / Q000378:metabolism*; D051379:Mice
D000418:Albumins; D008076:Cholesterol, HDL; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D007004:Hypoglycemic Agents; C048496:N(6)-carboxymethyllysine; D008687:Metformin; D008239:Lysine; C004479:pimagedine