on October 27, 2005
Published online before print October 27, 2005, doi: 10.1161/01.ATV.0000193618.32611.8b
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Submitted on August 1, 2005
Accepted on October 17, 2005
Cholesteryl Esters of Aggregated LDL Are Internalized by Selective Uptake in Human Vascular Smooth Muscle Cells
V. Llorente-Cortés ;
From the Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
* To whom correspondence should be addressed. E-mail: lbadimon{at}csic-iccc.santpau.es.
Objective--Low-density lipoprotein (LDL) receptor-related protein (LRP1) mediates the internalization of aggregated LDL (agLDL)-LDL trapped in the arterial intima bound to proteoglycans-into human vascular smooth muscle cells (VSMC). LRP1-mediated agLDL uptake induces high-intracellular cholesteryl ester (CE) accumulation. The aim of this study was to characterize the mechanism of agLDL internalization in human VSMC.
Methods and Results--The lipidic component of LDL was labeled with [3H] and the apolipoprotein component with [125I]. We found that >90% of intracellular CE derived from agLDL uptake was not associated with apoB100 degradation but was selectively taken up from agLDL. The inhibition of LRP1 expression by small interfering RNA treatment led to a decrease of 80±0.05% in agLDL-CE selective uptake. AgLDL induced intracellular CE accumulation without a concomitant CE synthesis. Cytosolic and cytoskeletal proteins were not required for CE transport. Electron and confocal microscopy experiments indicate that CE derived from agLDL accumulated in adipophilin-stained lipid droplets that were not removable by high-density lipoprotein.
Conclusions--Taken together, these results demonstrate that LRP1 mediates the selective uptake of CE from agLDL and that CE derived from agLDL is not intracellularly processed but stored in lipid droplets in human VSMC.
Key words: LRP1 • selective uptake • cholesteryl ester • adipophilin • aggregated LDL • HDL
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