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Title: Molecular etiology of atherogenesis--in vitro induction of lipidosis in macrophages with a new LDL model
Authors: Estronca, Luís 
Silva, Joao Carlos Pinho
Sampaio, Julio L.
Shevchenko, Andrej
Verkade, Paul
Vaz, Alfin D. N.
Vaz, Winchil L. C. 
Vieira, Otília V. 
Issue Date: 2012
Publisher: Public Library of Science
Project: Research grant PTDC/SAU/MII/66285/2006 
SFRH/BPD/26843/ 2006 
TRR 83 grant from the Deutsche Forschungsgemeinschaft 
Virtual Liver grant (Code/0315757) from the Bundesministerium fu¨ r Bildung und Forschung 
Serial title, monograph or event: PLoS ONE
Volume: 7
Issue: 4
Abstract: Background: Atherosclerosis starts by lipid accumulation in the arterial intima and progresses into a chronic vascular inflammatory disease. A major atherogenic process is the formation of lipid-loaded macrophages in which a breakdown of the endolysomal pathway results in irreversible accumulation of cargo in the late endocytic compartments with a phenotype similar to several forms of lipidosis. Macrophages exposed to oxidized LDL exihibit this phenomenon in vitro and manifest an impaired degradation of internalized lipids and enhanced inflammatory stimulation. Identification of the specific chemical component(s) causing this phenotype has been elusive because of the chemical complexity of oxidized LDL. Methodology/Principal Findings: Lipid ‘‘core aldehydes’’ are formed in oxidized LDL and exist in atherosclerotic plaques. These aldehydes are slowly oxidized in situ and (much faster) by intracellular aldehyde oxidizing systems to cholesteryl hemiesters. We show that a single cholesteryl hemiester incorporated into native, non-oxidized LDL induces a lipidosis phenotype with subsequent cell death in macrophages. Internalization of the cholesteryl hemiester via the native LDL vehicle induced lipid accumulation in a time- and concentration-dependent manner in ‘‘frozen’’ endolysosomes. Quantitative shotgun lipidomics analysis showed that internalized lipid in cholesteryl hemiester-intoxicated cells remained largely unprocessed in those lipid-rich organelles. Conclusions/Significance: The principle elucidated with the present cholesteryl hemiester-containing native-LDL model, extended to other molecular components of oxidized LDL, will help in defining the molecular etiology and etiological hierarchy of atherogenic agents.
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0034822
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais

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