Atherogenic properties of enzymatically degraded LDL: selective induction of MCP-1 and cytotoxic effects on human macrophages.
The mechanisms underlying the selective accumulation of macrophages in early atherosclerotic lesions are poorly understood but are likely to be related to specific properties of altered low density lipoprotein (LDL) deposited in the subendothelium. Enzymatic, nonoxidative degradation of LDL converts the lipoprotein to a potentially atherogenic moiety, enzymatically altered LDL (E-LDL), which activates complement and is rapidly taken up by human macrophages via a scavenger receptor-dependent pathway. Immunohistological evidence indicates that E-LDL is present in an extracellular location in the early lesion. We report that E-LDL causes massive release of monocyte chemotactic protein 1 (MCP-1) from macrophages and that expression of interleukin 8 or RANTES remains unchanged. Release of MCP-1 was preceded by a rapid expression of MCP-1 mRNA, which was detectable after 15 minutes, reached maximum levels after 1 hour, and remained detectable for 12 hours after exposure to concentrations as low as 10 microg/mL E-LDL. MCP-1 mRNA induction and protein release by E-LDL exceeded that evoked by oxidized LDL. Release of MCP-1 was dependent on de novo protein synthesis and on the activity of tyrosine kinases. At higher concentrations, E-LDL, but not oxidized LDL, exerted toxic effects on macrophages that in part appeared to be due to apoptosis. The results show that E-LDL possesses major properties of an atherogenic lipoprotein.
Klouche
M
M
Institute of Medical Microbiology and Hygiene, Johannes-Gutenberg University of Mainz, Germany. klouche@mail.Uni-Mainz.de
Gottschling
S
S
Gerl
V
V
Hell
W
W
Husmann
M
M
Dorweiler
B
B
Messner
M
M
Bhakdi
S
S
D001161:Arteriosclerosis / Q000209:etiology*; D016923:Cell Death; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D009439:Neuraminidase / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012194:RNA-Directed DNA Polymerase; D002787:Sterol Esterase / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
D018932:Chemokine CCL2; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D012194:RNA-Directed DNA Polymerase; D006867:Hydrolases; D002787:Sterol Esterase; D009439:Neuraminidase; D014357:Trypsin