D609 inhibits progression of preexisting atheroma and promotes lesion stability in apolipoprotein e-/- mice: a role of phosphatidylcholine-specific phospholipase in atherosclerosis.
OBJECTIVE
Atherosclerosis is considered to be a chronic inflammatory disease. Previous research has demonstrated that phosphatidylcholine-specific phospholipase C (PC-PLC) plays critical roles in various inflammatory responses. However, the association between PC-PLC and atherosclerosis is undetermined. Therefore, we sought to investigate whether PC-PLC was implicated in atherosclerosis.


RESULTS
Immunofluorescence analysis revealed an upregulation of PC-PLC in the aortic endothelium from apolipoprotein E-deficient (apoE(-/-)) mice. PC-PLC level and activity were also increased in human umbilical vein endothelial cells in response to oxidized low-density lipoprotein treatment. Pharmacological blockade of PC-PLC by D609 inhibited the progression of preexisting atherosclerotic lesions in apoE(-/-) mice and changed the lesion composition into a more stable phenotype. Using a combination of pharmacological inhibition, polyclonal antibodies, confocal laser scanning microscopy and Western blotting, we demonstrated that PC-PLC was required for endothelial expression of lectin-like oxidized low-density lipoprotein receptor-1. In addition, D609 treatment significantly decreased the aortic endothelial expression of the vascular cell adhesion molecule-1 and the intercellular adhesion molecule-1. Furthermore, inhibition of PC-PLC in human umbilical vein endothelial cells reduced the oxidized low-density lipoprotein induced expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemotactic protein-1.


CONCLUSIONS
Our data suggest that PC-PLC contributes to the progression of atherosclerosis.
Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
Lu
L
Zhang
Jing
J
Zhao
Le
L
Su
Bin
B
Huang
Li
L
Wang
Hua
H
Su
Yun
Y
Zhang
Shangli
S
Zhang
Junying
J
Miao
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009636:Norbornanes; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology / Q000627:therapeutic use*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D001057:Apolipoproteins E; D001952:Bridged-Ring Compounds; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D008077:Lipoproteins, LDL; D009636:Norbornanes; D013859:Thiocarbamates; D013871:Thiones; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; D018799:Intercellular Adhesion Molecule-1; C046498:tricyclodecane-9-yl-xanthogenate; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C