Cardiovascular disease represents the leading cause of morbidity and mortality among individuals affected by diabetes mellitus (DM). Advanced glycation endproducts (AGEs), generated from glycated proteins, exhibit elevated levels in DM patients and have been suggested to be among the responsible for the development of atherosclerosis. Consequently, a possible relationship among glycated human serum albumin (HSA), endoplasmatic reticulum (ER) stress, and cholesterol efflux in macrophages can be reasonably hypothesized. A series of in vitro investigation on these aspects has been published, focused on ATP-binding cassette transporters A1 and G1 which are involved in cholesterol efflux from cells to high density lipoproteins and apolipoprotein A1. In order to further study these aspects a series of experiments have been performed. Glycation levels of HSA isolated from healthy and diabetic type 1 (DM1) and type 2 (DM2) subjects were measured by matrix assisted laser desorption/ionization mass spectrometry and used for the further investigations. By this analytical approach it was observed that HSA from DM patients showed a mean condensation of at least 8 and 5 glucose units in type 1 and type 2 diabetics, respectively. Mouse peritoneal macrophages were treated with these HSA samples and ER stress and cholesterol efflux were evaluated. The expression levels of ER stress markers were found to be significantly higher in macrophages treated with glycated HSA while cholesterol efflux, via ABCA1, was significantly reduced. These experiments indicate that glycated HSA can contribute to atherosclerosis in diabetic patients by impairing cholesterol efflux and inducing ER stress in macrophages.
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