Modified lipoproteins, cytokines and macrovascular disease in non-insulin-dependent diabetes mellitus.
The processes of glycation and oxidation play a significant role in the acceleration of atherosclerosis in diabetes mellitus. Glycation is thought not only to increase the susceptibility of low-density lipoprotein (LDL) to oxidation but also to enhance the propensity of vessel wall structural proteins to bind extravasated plasma proteins, including LDL, and thus to contribute to a more marked oxidative modification of LDL. Glycated and oxidized lipoproteins induce cholesteryl ester accumulation in human macrophages and may promote platelet and endothelial 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 complexes containing LDL. Both the modified lipoproteins and the immune complexes formed with autoantibodies reactive with modified lipoproteins may be responsible for several alternative and not mutually exclusive pathways leading to foam cell formation, macrophage activation and endothelial cell damage and may thus be of potential significance in initiating and/or contributing to the acceleration of the development of atherosclerosis. In this review we discuss how modified LDL affects lipoprotein metabolism, how immune complexes containing LDL induce the transformation of macrophages into foam cells and promote macrophage activation leading to the release of cytokines and thus initiating a sequence 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 paradoxical increase in LDL-receptor expression thus further impairing cholesterol homeostasis and enhancing the development of atheromatous lesions.
Lopes-Virella
M F
MF
Ralph H. Johnson Department of Veterans Affairs Medical Center, Charieston, SC 29403, USA.
Virella
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G
D001161:Arteriosclerosis / Q000150:complications / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D008074:Lipoproteins / Q000145:classification / Q000378:metabolism*; D016491:Peripheral Vascular Diseases / Q000150:complications* / Q000276:immunology / Q000503:physiopathology
D016207:Cytokines; D008074:Lipoproteins