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Ligands of peroxisome proliferator-activated receptor-gamma increase the generation of vascular endothelial growth factor in vascular smooth muscle cells and in macrophages

100%

Jozkowicz A., Dulak J., Piatkowska E., Placha W., Dembinska-Kiec A.

Acta Biochimica Polonica

2000

tom 47

nr 4

Peroxisome proliferator-activated receptors-gamma (PPARgamma) are ligand-inducible transcription factors of the nuclear hormone receptor superfamily. We examined the effect of PPARgamma activation on the generation of vascular endothelial growth factor (VEGF), one of the major angiogenic agents. Rat vascular smooth muscle cells (VSMC) and murine macrophages RAW264.7 were incubated for 24 h with PPARgamma activators: prostaglandin J2 and ciglitazone. PPARgamma were expressed in VSMC and RAW cells and their activity was upregulated in the presence of PGJ2 and ciglitazone. Incubation of the cells with PPARgamma activators significantly augmented the release of VEGF protein into the media, both in resting and in IL-1beta- or LPS-stimulated cultures. The higher protein generation was connected with the increased expression of mRNA and transcriptional activation of VEGF promoter. We conclude that the activation of PPARgamma upregulates the generation of VEGF and may be involved in the regulation of angiogenesis.

Prostaglandin-J2 upregulates expression of matrix metalloproteinase-1 independently of activation of peroxisome proliferator-activated receptor-gamma

100%

Jozkowicz A., Huk I., Nigisch A., Cisowski J., Weigel G., Dulak J.

Acta Biochimica Polonica

2003

tom 50

nr 3

Peroxisome proliferator-activated receptor-y (PPARy) is a ligand-inducible nuclear receptor that functions as a transcription factor involved in lipid metabolism, inflammatory response and angiogenesis. The most potent endogenous PPARγ activator is 15-deoxy-Δ12,14,prostaglandin-J2 (15d-PGJ2), whereas synthetic ligands include the oral antidiabetic drugs thiazolidinediones (TZDs). Activation of PPARγ was reported to decrease the synthesis of matrix metalloproteinases (MMPs) in vascular smooth muscle cells and macrophages. We aimed to investigate the effect of PPARy ligands on expression of MMP-1 and urokinase plasminogen activator (uPA) in human microvascular endothelial cells (HMEC-1). We found that treatment of HMEC-1 with 15d-PGJ2 increased the synthesis of MMP-1 protein up to 168% comparing to untreated cells. TZDs (ciglitazone and troglitazone), more potent activators of PPAR in HMEC-1, did not influence MMP-1 production, arguing against the involvement of PPAR in this process. Importantly, the stimulatory effect of 15d-PGJ2 was reversed by the antioxidant N-acetyl-cysteine (NAC), suggesting a contribution of oxidative stress. We demonstrated also that 15d-PGJ2 did not change the activity of MMP-1 promoter, but increased the stability of MMP-1 mRNA. In contrast, 15d-PGJ2 very potently inhibited the synthesis of uPA. This effect was in part mimicked by ciglitazone and troglitazone implying an involvement of PPAR. Accordingly, NAC did not modify the inhibitory effect of 15d-PGJ2 on uPA expression. In conclusion, we postulate that 15d-PGJ2 may differently regulate the synthesis of proteases involved in angiogenesis: it upregulates MMP-1 expression in HMEC-1 through induction of oxidative stress, and inhibits uPA synthesis partly by activation of PPARγ.

15-deoxy-delta12,14-prostaglandin J2 suppresses RANTES expression by inhibiting NADPH oxidase activation in Helicobater pylori-infected gastric epithelial cells

80%

Cha B., Lim J. W., Kim K. H., Kim H.

Journal of Physiology and Pharmacology

2011

tom 62

nr 2

Peroxisome proliferators-activated receptor-g (PPAR-g) is a ligand-activated transcription factor. 15 deoxy-12,14 prostaglandin J2 (15d-PGJ2) is a potent PPAR- ligand and acts as an anti-inflammatory agent via PPAR--dependent and independent mechanisms. Helicobacter pylori (H. pylori) induces gastric inflammation by inducing the activation of oxidant-sensitive transcription factor NF-B and cytokine expression in gastric epithelial cells. Since 15d-PGJ2 inhibits NF-B activation in various cells, it may suppress H. pylori-induced inflammatory signaling and cytokine expression in gastric epithelial cells. The present study aims to determined the effect of 15d-PGJ2 on the activation of inflammatory mediators Jak/Stat (Janus kinase/signal transducers and activators of transcription) and induction of cytokine RANTES in H. pylori-infected gastric epithelial AGS cells. Since NADPH oxidase is a candidate for the production of reactive oxygen species in H. pylori-infected gastric epithelial cells, we determined the effect of 15d-PGJ2 on the activation of NADPH oxdase. AGS cells were cultured in the presence of H. pylori treated with or without 15d-PGJ2. The activations of NADPH oxidase and Jak1/Stat3, the levels of H2O2 and RANTES in the medium, and DNA binding activity of Stat3 were assessed. A Jak/Stat3 specific inhibitor AG490 and an inhibitor of NADPH oxidase diphenyleneiodonium (DPI) were treated to determine the direct involvement of Jak/Stat and NADPH oxidase on the production of H2O2 and RANTES in H. pylori-infected cells. H. pylori induced the production of H2O2 and RANTES as well as the activations of NADPH oxidase and Jak1/Stat3, which were inhibited by the treatment of 15d-PGJ2. DPI suppressed H. pylori-induced alterations similar to 15d-PGJ2. However, AG490 had no effect on NADPH oxidase activation, but reduced the level of RANTES in the medium released from H. pylori-infected cells. Conclusion: NADPH oxidase activation is an upstream signaling of Jak1/Stat3 activation and induction of RANTES in H. pylori-infected AGS cells. 15d-PGJ2, inhibits the activations of NADPH oxidase and Jak1/Stat3 and RANTES expression, suggesting that 15d-PGJ2 may be beneficial for the treatment of H. pylori-induced gastric inflammation.

Ograniczanie wyników

2 Acta Biochimica Polonica

1 Journal of Physiology and Pharmacology

2 Dulak J.

2 Jozkowicz A.

1 Cha B.

1 Cisowski J.

1 Dembinska-Kiec A.

1 Huk I.

1 Kim H.

1 Kim K. H.

1 Lim J. W.

1 Nigisch A.

1 Piatkowska E.

1 Placha W.

1 Weigel G.

1 2011

1 2003

1 2000

Wyniki wyszukiwania

Ligands of peroxisome proliferator-activated receptor-gamma increase the generation of vascular endothelial growth factor in vascular smooth muscle cells and in macrophages

Prostaglandin-J2 upregulates expression of matrix metalloproteinase-1 independently of activation of peroxisome proliferator-activated receptor-gamma

15-deoxy-delta12,14-prostaglandin J2 suppresses RANTES expression by inhibiting NADPH oxidase activation in Helicobater pylori-infected gastric epithelial cells