Abstract
In this study, we examined the possibility of glycoxidation and lipid peroxidation of low density lipoprotein in atherosclerotic lesions in vivo and in vitro, in order to clarify their role in the pathogenesis of diabetic macroangiopathy. NIDDM patients showed a greater increase in hemoglobin Alc in plasma and carboxymethyllysine (CML), a glycoxidation product, in collagen of an internal thoracic artery than nondiabetic controls. The level of CML significantly correlated with that of hemoglobin Alc in plasma. An immunochemical analysis showed that CML and oxidized phosphatidylcholine (oxPC), one of lipid peroxidation products, were formed in human low density lipoprotein (LDL) which was incubated with copper ion and glucose in vitro. The amount of CML increased in LDL in dose dependent manner of copper ion and glucose added. However, the formation of oxPC depended on the concentration of copper ion, but was independent of the glucose concentration. The formation of CML was completely inhibited either by chelators or by aminoguanidine. On the other hand, the formation of oxPC was completely inhibited by chelators, but partially protected by aminoguanidine. An immunohistochemical analysis demonstrated that CML, oxPC and malondialdehyde (MDA) mainly accumulated in macrophage/foam cells and atheroma, while pyrraline, one of nonoxidative products of glycation, localized in the extracellular matrix in atherosclerotic lesions. These results suggest that the glycoxidation and lipid peroxidation of LDL may synergistically promote the development of atherosclerotic lesions, which may thus contribute to the progression of diabetic macroangiopathy.
