Thiazolidinediones Down-Regulate Plasminogen Activator Inhibitor Type 1 Expression in Human Vascular Endothelial Cells: A Possible Role for PPARγ in Endothelial Function

Kato, Ken; Satoh, Hiroaki; Endo, Yuki; Yamada, Daishiro; Midorikawa, Sanae; Sato, Wakano; Mizuno, Kenji; Fujita, Teizo; Tsukamoto, Kazuhisa; Watanabe, Tsuyoshi

doi:10.1006/bbrc.1999.0648

Cited by 146 publications

(68 citation statements)

References 19 publications

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“…10 PPAR␥ is expressed by human endothelial cells, including HUVECs. 5 Activation of this receptor can inhibit endothelial cell proliferation and may modulate PAI-1 expression, 5,11 reduce endothelin-1 production, 12 and induce apoptosis, 13 in particular in serum-free conditions. Activation of PPAR␥ results in inhibition of the AP-1 and NF-B pathways 3,12 that regulate the expression of adhesion molecules by activated endothelial cells.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Moreover, another group showed that treatment of women with the polycystic ovary syndrome (PCOS) with troglitazone significantly decreased plasma PAI-1 protein concentration and activity [20]. Very recently, it has been shown that troglitazone and pioglitazone inhibit PAI-1 expression and secretion in human endothelial cells after TNF-a stimulation [21].…”

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confidence: 99%

Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes

2000

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Obesity is frequently associated with a cluster of cardiovascular risk factors that includes insulin resistance, impaired glucose tolerance or Type II (non-insulin-dependent) diabetes mellitus, high blood pressure, hypertriglyceridaemia and low HDL-cholesterol [1]. Among the multiple mechanisms which could explain the relation between insulin resistance and cardiovascular disease, disorders of the fibrinolytic system seem to play an important part [2]. The impairment of fibrinolysis in insulin resistance and Type II diabetes is characterized by increases in plasma plasminogen activator inhibitor (PAI-1) antigen and its activity [2]. Abstract Aims/hypothesis. Increased plasma plasminogen activator inhibitor-1 (PAI-1) concentrations are characteristic for subjects with insulin resistance and could contribute to the increased cardiovascular risk in this state. In this study, we investigated the effect of troglitazone, a ligand of the nuclear receptor peroxisome proliferator activated receptor-g, on PAI-1 expression and secretion in human adipocytes. Methods. We used two models: in vitro differentiated subcutaneous and omental adipocytes cultured under serum-free conditions and isolated subcutaneous and omental fat cells kept in suspension culture. Plasminogen activator inhibitor-1 protein was measured by ELISA, PAI-1 mRNA by a semiquantitative RT-PCR technique. Results. Exposure of in vitro differentiated subcutaneous adipocytes from young normal-weight females to 1 mg/ml troglitazone for 72 h caused a reduction of both PAI-1 secretion (by 29 5 %; p < 0.01) and PAI-1 mRNA expression (by 26 3 %; p < 0.05). In cultures from severely obese subjects, troglitazone induced a decrease of PAI-1 antigen secretion from newly differentiated omental adipocytes by 49 8 % (p < 0.01) and from subcutaneous adipocytes by 30 7 % (p < 0.05). Exposure of freshly isolated subcutaneous and omental adipocytes in suspension culture to troglitazone induced a similar reduction of PAI-1 concentration in the culture medium (by 35 11 %, p < 0.05. and 33 8 %, p < 0.05 compared with control, respectively). Conclusion/interpretation. This study provides evidence that troglitazone reduces PAI-1 production in human adipocytes, probably at the transcriptional level. This observation could point to a new beneficial effect of troglitazone, particularly in obese subjects, which could be associated with a reduced cardiovascular risk. [Diabetologia (2000)

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“…TZDs are ligands for the transcription factor peroxisome proliferator-activated receptor-γ (PPARγ), a member of the nuclear receptor superfamily. PPARγ is expressed predominantly in adipose tissue, but also in macrophages, beta cells of the pancreas, endothelial cells and other tissues (Kato et al 1999;Kersten et al 2000). The Olefsky group noted increased insulin sensitivity and lower blood pressure in obese patients without diabetes who were treated with troglitazone (Nolan et al 1994).…”

Section: Rationale For the Combined Use Of Thiazolidinediones And Metmentioning

confidence: 99%

“…PPAR gamma is expressed in endothelial cells, and may have important role in vascular restenosis (reviewed in (Bruemmer et al 2005). In cultured endothelial cells ligand activation of PPAR gamma has been shown to inhibit thrombin-induced endothelin-1 production (Delerive et al 1999) and plasminogen activator inhibitor type 1 expression (Kato et al 1999). In people, progression of carotid intima-media thickness, a marker of atherosclerotic disease, is improved with pioglitazone (Mazzone et al 2006).…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes

Stafford

Elasy²

2007

VHRM

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Type 2 diabetes mellitus (DM2) is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce suffi cient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT) to frank diabetes mellitus, refl ecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs) are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefi ts beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use.

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Thiazolidinediones Down-Regulate Plasminogen Activator Inhibitor Type 1 Expression in Human Vascular Endothelial Cells: A Possible Role for PPARγ in Endothelial Function

Cited by 146 publications

References 19 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

Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes

Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes

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