Abstract
Aggregation and fusion of lipoproteins trigger subendothelial retention of cholesterol, promoting atherosclerosis. The tendency of a lipoprotein to form fused particles is considered to be related to its atherogenic potential. We aimed to isolate and characterize aggregated and nonaggregated subfractions of LDL from human plasma, paying special attention to particle fusion mechanisms. Aggregated LDL was almost exclusively found in electronegative LDL (LDL(-)), a minor modified LDL subfraction, but not in native LDL (LDL(+)). The main difference between aggregated (agLDL(-)) and nonaggregated LDL(-) (nagLDL(-)) was a 6-fold increased phospholipase C-like activity in agLDL(-). agLDL(-) promoted the aggregation of LDL(+) and nagLDL(-). Lipoprotein fusion induced by α-chymotrypsin proteolysis was monitored by NMR and visualized by transmission electron microscopy. Particle fusion kinetics was much faster in agLDL(-) than in nagLDL(-) or LDL(+). NMR and chromatographic analysis revealed a rapid and massive phospholipid degradation in agLDL(-) but not in nagLDL(-) or LDL(+). Choline-containing phospholipids were extensively degraded, and ceramide, diacylglycerol, monoacylglycerol, and phosphorylcholine were the main products generated, suggesting the involvement of phospholipase C-like activity. The properties of agLDL(-) suggest that this subfraction plays a major role in atherogenesis by triggering lipoprotein fusion and cholesterol accumulation in the arterial wall.
Highlights
Atherosclerosis is a consequence of the excessive deposition of cholesterol in the intimal vessel wall, coming mainly from
It is widely accepted that lipoprotein retention mediated by the binding of LDL to proteoglycans is a key event in atherogenesis [1]
Special attention was paid to the mechanism of particle fusion because this feature plays a key role in subendothelial lipoprotein retention [20]
Summary
Atherosclerosis is a consequence of the excessive deposition of cholesterol in the intimal vessel wall, coming mainly from. Oxidation of LDL is the most widely studied mechanism of modification, and oxidized lipids play a central role in inflammation, proliferation, and apoptosis [3] Other modifications, such as degradation by phospholipases, cholesteryl esterase, or proteases, occur in the intima of the arterial wall and have a more relevant role than oxidation in lipoprotein trapping [4]. LDL(Ϫ) fractions with increased affinity to proteoglycans presented a higher content of aggregated particles This finding suggests that an aggregated subfraction of LDL(Ϫ) could be retained more strongly in the arterial wall than the bulk of nonaggregated LDL(Ϫ). This activity makes this subfraction prone to particle fusion and promotes the aggregation of nonaggregated LDL subfractions These properties suggest that the aggregated LDL(Ϫ) subfraction has a major atherogenic role, favoring subendothelial cholesterol accumulation
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