Effects of peroxisome proliferator-activated receptor ligands in modulating tissue factor and tissue factor pathway inhibitor in acutely symptomatic carotid atheromas.
OBJECTIVE
Severely stenotic, symptomatic carotid atheromas are associated with a high risk of stroke in the short term. Although carotid endarterectomy is effective in reducing this stroke risk, it is frequently not applied within the time window for significant benefit. We investigated the effect of peroxisome proliferator-activated receptor (PPAR) -alpha and -gamma ligands in acutely modifying tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in unstable carotid atheromas.


METHODS
During a 3-year period, 64 patients who had experienced a transient ischemic attack or stroke with good recovery within 6 weeks before surgery and 12 asymptomatic patients with a >70% carotid stenosis were recruited. The expression of PPAR-alpha and -gamma was investigated in endarterectomy samples. The effects of the PPAR-alpha and -gamma ligands fenofibrate and rosiglitazone were investigated in cell culture experiments. Targeted biopsy specimens from endarterectomy samples (n=48) were incubated with medication for 4 days. TF and TFPI were assessed by immunohistochemistry, Western blot analysis, flow cytometry, and activity assays.


RESULTS
PPAR-gamma1 but not -alpha was downregulated in atheromas removed from patients with recent symptoms and no evidence of diabetes. Fenofibrate but not rosiglitazone impaired the induction of TF in human endothelial cells and reduced resting levels of TF activity in vascular smooth muscle cells. Rosiglitazone but not fenofibrate increased TFPI secretion from human endothelial cells. Both fenofibrate (100+/-18.7% to 56.6+/-8.8%, P=0.005; 0.2664+/-0.0696 to 0.1771+/-0.0310, P=0.02) and rosiglitazone (100+/-22% to 88.3+/-20%, P=0.02; 0.3113+/-0.0729 to 0.2287+/-0.0415, P=0.04) reduced TF expression and activity, respectively, in atheroma biopsy specimens. A low expression of TFPI was found in atheroma biopsy specimens with little evidence of TFPI activity.


CONCLUSIONS
This study suggests that both PPAR-alpha and -gamma ligands have beneficial effects in acutely reducing TF in unstable carotid atheromas.
Golledge
Jonathan
J
Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Queensland, Australia. Jonathan.Golledge@jcu.edu.au
Mangan
Simone
S
Clancy
Paula
P
D000368:Aged; D000369:Aged, 80 and over; D016893:Carotid Stenosis / Q000150:complications / Q000503:physiopathology*; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D006801:Humans; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000503:physiopathology; D008024:Ligands; D008074:Lipoproteins / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction; D020521:Stroke / Q000209:etiology / Q000503:physiopathology; D045162:Thiazolidinediones / Q000494:pharmacology; D013925:Thromboplastin / Q000187:drug effects / Q000378:metabolism*
D008024:Ligands; D008074:Lipoproteins; D047493:PPAR alpha; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; C051928:lipoprotein-associated coagulation inhibitor; D000077154:Rosiglitazone; D013925:Thromboplastin; D011345:Fenofibrate