Mf. Lopesvirella et G. Virella, MODIFIED LIPOPROTEINS, CYTOKINES AND MACROVASCULAR DISEASE IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS, Annals of medicine, 28(4), 1996, pp. 347-354
The processes of glycation and oxidation play a significant role in th
e acceleration of atherosclerosis in diabetes mellitus. Glycation is t
hought not only to increase the susceptibility of low-density lipoprot
ein (LDL) to oxidation but also to enhance the propensity of vessel wa
ll structural proteins to bind extravasated plasma proteins, including
LDL, and thus to contribute to a more marked oxidative modification o
f LDL. Glycated and oxidized lipoproteins induce cholesteryl ester acc
umulation in human macrophages and may promote platelet and endothelia
l cell dysfunction. Furthermore, these modified lipoproteins have the
ability to trigger an autoimmune response that leads to the formation
of autoantibodies and subsequently to the formation of immune complexe
s containing LDL. Both the modified lipoproteins and the immune comple
xes formed with autoantibodies reactive with modified lipoproteins may
be responsible for several alternative and not mutually exclusive pat
hways leading to foam cell formation, macrophage activation and endoth
elial cell damage and may thus be of potential significance in initiat
ing and/or contributing to the acceleration of the development of athe
rosclerosis. In this review we discuss how modified LDL affects lipopr
otein metabolism, how immune complexes containing LDL induce the trans
formation of macrophages into foam cells and promote macrophage activa
tion leading to the release of cytokines and thus initiating a sequenc
e of events leading to endothelial cell damage and to the recruitment
and activation of leucocytes. We also summarize our work showing that
macrophage activation by LDL containing immune complexes leads to a pa
radoxical increase in LDL-receptor expression thus further impairing c
holesterol homeostasis and enhancing the development of atheromatous l
esions.