Potent Inhibitory Effect of Troglitazone on Carotid Arterial Wall Thickness in Type 2 Diabetes

Minamikawa, Jun

doi:10.1210/jc.83.5.1818

Cited by 209 publications

(114 citation statements)

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“…18 However, atherosclerosis is a composite phenomenon involving many different molecular pathways, and further studies are needed to assess the effects of PPAR␥ activators on the progression of atherosclerosis. …”

Section: Pasceri Et Al Ppar␥ and Vascular Inflammation 237mentioning

confidence: 99%

Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator–Activated Receptor-γ Activators

et al. 2000

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Background-Peroxisome proliferator-activated receptor-␥ (PPAR␥) is expressed in atherosclerotic plaques and in endothelial cells. The possible effects of PPAR␥ activators on endothelial activation and inflammatory response within the plaque are currently unknown. Methods and Results-We tested the hypothesis that PPAR␥ activators inhibit vascular cell adhesion molecule and intercellular adhesion molecule (ICAM-1) expression in cultured endothelial cells (evaluated by flow cytometry) and homing of monocyte/macrophages to atherosclerotic plaques in vivo. In endothelial cells, the PPAR␥ agonists troglitazone at 100 mol/L and 15-deoxy-⌬12,14 -prostaglandin J 2 (15d-PGJ2) at 20 mol/L markedly attenuated the tumor necrosis factor-induced expression of VCAM-1 and ICAM-1. A significant inhibition of VCAM-1 expression was also evident at 5 and 10 mol/L 15d-PGJ2 and 20 mol/L troglitazone. Expression of E-selectin and PECAM-1 was not altered. To confirm the biological relevance of these results, we assessed the effects of troglitazone on monocyte/macrophage homing to atherosclerotic plaques in apoE-deficient mice. A 7-day treatment with troglitazone (400 mg/kg) significantly reduced monocyte/macrophage homing to atherosclerotic plaques (236Ϯ77 versus 177Ϯ43 macrophages, Pϭ0.03); an even more striking inhibition was found at 3200 mg/kg troglitazone (344Ϯ76 versus 172Ϯ83 macrophages, Pϭ0.005). Conclusions-PPAR␥

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Section: Pasceri Et Al Ppar␥ and Vascular Inflammation 237mentioning

confidence: 99%

Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator–Activated Receptor-γ Activators

et al. 2000

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“…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%

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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“…The potentially anti-atherogenic effects mediated by PPARg include cholesterol removal through ATP binding cassette transporter A 1 (ABCA1) (13) and anti-inflammatory effects such as the repression of phorbol ester-stimulated expression of interleukin-6 and -1b, tumour necrosis factor-a, gelatinase and scavenger receptor-A (4,15). Furthermore, there is direct experimental evidence that PPARg activation can improve atherosclerosis (16) and human data showing that thiazolidinedione treatment led to a significant reduction of carotid artery wall thickness in patients with type 2 diabetes (18). These data suggest that PPARg is a candidate gene for a possible link between altered lipid and glucose metabolism, such as in patients with diabetes mellitus, and atherosclerosis development.…”

Section: Introductionmentioning

confidence: 99%

Lack of association between peroxisome proliferator-activated receptor-gamma-2 gene variants and the occurrence of coronary heart disease in patients with diabetes mellitus

Blüher

Klemm

Gerike³

et al. 2002

European Journal of Endocrinology

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Objective: Recent evidence indicates that peroxisome proliferator-activated receptor-g (PPARg) is expressed at high levels in foam cells of atherosclerotic lesions, that PPARg agonists may directly modulate vessel wall function and that mutations in the PPARg-2 gene are associated with a reduced risk of coronary artery disease. Methods: We investigated whether known variants in the PPARg-2 gene are associated with the occurrence of coronary heart disease (CHD) in 365 patients with type 2 diabetes, prospectively characterised for the presence or absence of CHD. The Pro115Gln, Pro12Ala, Pro467Leu, Val290Met mutations and two polymorphisms C478T and C161T of the PPARg-2 gene were examined using PCR, denaturing gradient gel electrophoresis and direct sequencing. Results: The distribution of the Pro12Ala, Ala12Ala, C161T and T161T variants was not significantly different between patients with and without CHD, independent of the gender. The Pro12Ala ðP ¼ 0:011Þ and the Ala12Ala ðP ¼ 0:006Þ variant were associated with a higher body mass index (BMI) compared with the Pro12Pro genotype. A multiple logistic regression analysis introducing the typical risk factors for CHD (age, sex, hypertension, smoking, BMI .26 kg/m 2 , elevated low density lipoprotein cholesterol and haemoglobin A 1 c .7%) identified age .60, male gender, hypertension and a higher BMI, but not the PPARg-2 variants, as significant risk factors for CHD in our study groups. Conclusion: The PPARg-2 genotype was not associated with an increased or reduced risk of the occurrence of CHD and can therefore not be regarded as an independent risk factor for CHD in patients with diabetes mellitus.

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Potent Inhibitory Effect of Troglitazone on Carotid Arterial Wall Thickness in Type 2 Diabetes

Cited by 209 publications

References 0 publications

Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator–Activated Receptor-γ Activators

Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator–Activated Receptor-γ Activators

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

Lack of association between peroxisome proliferator-activated receptor-gamma-2 gene variants and the occurrence of coronary heart disease in patients with diabetes mellitus

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