Thiazolidinediones reduce the LDL binding affinity

Authors: L R Tannock P J Little C Tsoi P H R Barrett T N Wight A Chait

Publish Date: 2004/04/08

Volume: 47, Issue: 5, Pages: 837-843

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Abstract

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 bindingPrimate aortic smooth muscle cells were exposed to troglitazone or rosiglitazone or no stimulus at all for a 24hour steadystate 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 determinedProteoglycans 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 cellsType 2 diabetes is characterised by hyperglycaemia insulin resistance and often central obesity Atherosclerotic complications continue to be a major cause of morbidity and mortality in persons with diabetes Thiazolidinediones a class of peroxisome proliferatoractivated receptor γ PPARγ ligands have been shown to decrease atherosclerosis in animal models 1 2 3 4 Thiazolidinediones have several potential antiatherogenic properties including inhibition of smooth muscle cell 5 and endothelial cell proliferation 6 improvements in fibrinolysis 7 and decreases in carotid artery intimamedia thickness 8 Although the effect of thiazolidinediones on clinical cardiovascular events in individuals with Type 2 diabetes is unknown due to the short duration of availability troglitazone was shown to inhibit the formation of atherosclerotic lesions in diabetic and nondiabetic male LDLreceptordeficient mice 2 The diabetic and nondiabetic mice differed in their glycaemic responses to troglitazone yet both groups had decreased lesion formation suggesting a direct vascular effect of troglitazone separate from its metabolic effects 2 Troglitazone supplementation also inhibited the formation of atherosclerotic lesions in male apolipoproteinEdeficient mice 1 Rosiglitazone was shown to decrease atherosclerosis development in male LDLreceptordeficient mice 3 and in diabetic and nondiabetic male apolipoproteinEdeficient mice 4 Troglitazone and rosiglitazone were shown to decrease the development of glomerulosclerosis in rats 9 10 11 In one of these studies the kidneys were stained for the glomerular mesangial basement membrane chondroitin sulphate proteoglycans and the data suggested that the inhibitory effect of troglitazone on diabetic glomerulosclerosis may be related to reduced proteoglycan synthesis 10

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