Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans.
OBJECTIVE
Retention of atherogenic lipoproteins in the artery wall by proteoglycans is a key step in the development of atherosclerosis. Thiazolidinediones have been shown to reduce atherosclerosis in mouse models. The aim of this study was to determine whether thiazolidinediones modify vascular proteoglycan synthesis in a way that decreases LDL binding.


METHODS
Primate aortic smooth muscle cells were exposed to troglitazone or rosiglitazone, or no stimulus at all for a 24-hour steady-state labelling period. Sulphate incorporation, size and LDL binding affinity of proteoglycans were determined. Proteoglycans secreted by cells in the presence or absence of troglitazone were separated into large and small classes by size exclusion chromatography, and LDL binding affinity was determined.


RESULTS
Proteoglycans synthesised by cells exposed to troglitazone or rosiglitazone were smaller, with decreased sulphate incorporation and decreased LDL binding affinity. However, troglitazone had a greater effect than rosiglitazone. Troglitazone reduced the LDL binding affinities of both the large and small proteoglycans compared with control. The binding differences persisted when glycosaminoglycan chains released from proteoglycans were incubated with LDL, indicating that troglitazone affects the glycosaminoglycan synthetic machinery of these cells.


CONCLUSIONS
Thiazolidinediones decrease the LDL binding affinity of the proteoglycans synthesised by primate aortic smooth muscle cells. This could, in part, account for the reduced atherosclerosis observed in animal models.
Tannock
L R
LR
Department of Medicine, University of Washington, Seattle, 98195, USA.
Little
P J
PJ
Tsoi
C
C
Barrett
P H R
PH
Wight
T N
TN
Chait
A
A
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000097:blood*; D008254:Macaca nemestrina; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D008077:Lipoproteins, LDL; D011509:Proteoglycans; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione; D000077288:Troglitazone