Peroxisome proliferator–activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor–deficient mice

Li, Andrew C.; Brown, Kathleen K.; Silvestre, Mercedes; Willson, Timothy M.; Palinski, Wulf; Glass, Christopher K.

doi:10.1172/jci10370

Cited by 811 publications

(629 citation statements)

References 43 publications

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“…This suggests that the observed effects of troglitazone on proteoglycan synthesis are due to its thiazolidinedione moiety, rather than to its α-tocopherol moiety. Several different thiazolidinediones have been reported to decrease atherosclerosis in animal models [1,2,3,4]. Therefore, we suggest that the effects of troglitazone on proteoglycan synthesis described here are class effects.…”

Section: Discussionmentioning

confidence: 55%

“…Troglitazone supplementation also inhibited the formation of atherosclerotic lesions in male apolipoprotein-E-deficient mice [1]. Rosiglitazone was shown to decrease atherosclerosis development in male LDL-receptor-deficient mice [3] and in diabetic and non-diabetic male apolipoprotein-E-deficient mice [4]. Troglitazone and rosiglitazone were shown to decrease the development of glomerulosclerosis in rats [9,10,11].…”

Section: Introductionmentioning

confidence: 95%

“…Atherosclerotic complications continue to be a major cause of morbidity and mortality in persons with diabetes. Thiazolidinediones, a class of peroxisome proliferator-activated receptor γ (PPARγ) ligands, have been shown to decrease atherosclerosis in animal models [1,2,3,4]. Thiazolidinediones have several potential anti-atherogenic properties, including inhibition of smooth muscle cell [5] and endothelial cell proliferation [6], improvements in fibrinolysis [7] and decreases in carotid artery intima-media thickness [8].…”

Section: Introductionmentioning

confidence: 99%

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Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans

et al. 2004

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Aims/hypothesis. 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/interpretation. 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.

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Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans

et al. 2004

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“…Rosiglitazone has also been reported to decrease plasma concentrations of C-reactive protein and matrix metalloproteinase-9 (Haffner et al, 2002), and inhibit the development of atherosclerosis in low-density lipoprotein receptor-deficient mice (Li et al, 2000). However, although there are a large number of studies reporting anti-inflammatory actions of PPAR ligands, some observations suggest that PPAR agonists may also have pro- Figure 5 Dose-dependent effects of PPARa agonists on iNOS protein expression in J774 macrophages.…”

Section: Discussionmentioning

confidence: 99%

PPARα agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS‐treated macrophages

Leppänen

Sareila

et al. 2007

British J Pharmacology

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Background and purpose: Nitric oxide (NO) production through the inducible nitric oxide synthase (iNOS) pathway is increased in response to pro-inflammatory cytokines and bacterial products. In inflammation, NO has pro-inflammatory and regulatory effects. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear steroid receptor superfamily, regulate not only metabolic but also inflammatory processes. The aim of the present study was to investigate the role of PPARa in the regulation of NO production and iNOS expression in activated macrophages. Experimental approach: The effects of PPARa agonists were investigated on iNOS mRNA and protein expression, on NO production and on the activation of transcription factors NF-kB and STAT1 in J774 murine macrophages exposed to bacterial lipopolysaccharide (LPS). Key results: PPARa agonists GW7647 and WY14643 reduced LPS-induced NO production in a dose-dependent manner as measured by the accumulation of nitrite into the culture medium. However, PPARa agonists did not alter LPS-induced iNOS mRNA expression or activation of NF-kB or STAT1 which are important transcription factors for iNOS. Nevertheless, iNOS protein levels were reduced by PPARa agonists in a time-dependent manner. The reduction was markedly greater after 24 h incubation than after 8 h incubation. Treatment with the proteasome inhibitors, lactacystin or MG132, reversed the decrease in iNOS protein levels caused by PPARa agonists. Conclusions and implications:The results suggest that PPARa agonists reduce LPS-induced iNOS expression and NO production in macrophages by enhancing iNOS protein degradation through the proteasome pathway. The results offer an additional mechanism underlying the anti-inflammatory effects of PPARa agonists.

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“…There may be situations, therefore, when scavenger receptors are important for inhibition or regression of atherosclerosis, and thus we concur with a recent review by van Berkel et al that makes the point that the net effect of SRA or CD36 expression in vivo can depend on other factors (2005). For example, treatment with rosiglitazone up regulated CD36 gene and protein expression in male LDLR KO mice, but this was in the context of up regulation of efflux proteins, which apparently enhanced lipoprotein clearance, decreased foam cell formation and reduced atherosclerotic lesion area (Li, Brown, Silvestre, Willson, Palinski, & Glass, 2000). This effect was not observed in female mice for reasons that remain unclear.…”

Section: Cd36 and Insulin Resistancementioning

confidence: 96%

CD36: Implications in cardiovascular disease

Febbraio

Silverstein

2007

The International Journal of Biochemistry & Cell Biology

215

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CD36 is a broadly expressed membrane glycoprotein that acts as a facilitator of fatty acid uptake, a signaling molecule, and a receptor for a wide range of ligands, including apoptotic cells, modified forms of low density lipoprotein, thrombospondins, fibrillar beta-amyloid, components of gram positive bacterial walls and malaria infected erythrocytes. CD36 expression on macrophages, dendritic and endothelial cells, and in tissues including muscle, heart, and fat, suggest diverse roles, and indeed, this is truly a multifunctional receptor involved in both homeostatic and pathologic conditions. Despite an impressive increase in our knowledge of CD36 functions, in depth understanding of the mechanistic aspects of this protein remains elusive. This review focuses on CD36 in cardiovascular disease-what we know, and what we have yet to learn.

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Peroxisome proliferator–activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor–deficient mice

Cited by 811 publications

References 43 publications

Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans

Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans

PPARα agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS‐treated macrophages

CD36: Implications in cardiovascular disease

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