Modulation of endothelial cell thrombomodulin by PPAR ligands--variation according to environment.
BACKGROUND
Thrombomodulin (TM) is an important anti-coagulant protein that is down-regulated on endothelial cells overlying atherosclerotic plaques. We investigated the effects of the peroxisome proliferator-activated receptor (PPAR) ligands, fenofibrate and rosiglitazone, on the expression of TM ex vivo by advanced carotid atheromas, and in vitro by endothelial cells.


METHODS
Adjacent carotid atheroma biopsies were incubated in vehicle control or PPAR ligand in explant culture for 4 days. Human aortic endothelial cells were incubated with PPAR ligands in vitro. TM expression was measured by Western blotting and flow cytometry. TM activity was assessed by generation of activated protein C.


RESULTS
The PPAR-alpha activator, fenofibrate, up-regulated total TM expression within carotid explants by 1.7-fold (P<0.001) with no effect on activity. Rosiglitazone treatment had no effect on protein levels but reduced activity by 73% of the control (P<0.05). We noted disparate effects of PPAR ligands in atheroma samples from different patients and postulated that the response of endothelial cells to medication was influenced by the atheromatous environment. Incubation of human aortic endothelial cells with fenofibrate alone led to a dose-dependent increase in TM expression (P<0.05), however, in the presence of oxidized LDL a dose-dependent reduction in TM expression was induced by fenofibrate (P<0.05).


CONCLUSIONS
The ability of fenofibrate to increase endothelial cell and carotid atheroma TM protein expression suggests a potential therapeutic role for this medication. The response to PPAR ligands likely varies depending on the exact constituents of individual atherosclerotic plaques, such as the relative amount of oxidized LDL.
Mangan
Simone
S
Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Queensland, 4811, Australia.
Clancy
Paula
P
Golledge
Jonathan
J
D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D016893:Carotid Stenosis / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D009924:Organ Culture Techniques; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D018180:Thrombomodulin / Q000378:metabolism*; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000187:drug effects
D008024:Ligands; D008077:Lipoproteins, LDL; D045162:Thiazolidinediones; D018180:Thrombomodulin; D000077154:Rosiglitazone; D011345:Fenofibrate