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

100%

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

2003

vol. 50

issue 3

677-689

Peroxisome proliferator-activated receptor-γ (PPARγ) 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-Δ12,14prostaglandin-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 PPARγ 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 PPARγ in HMEC-1, did not influence MMP-1 production, arguing against the involvement of PPARγ 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 PPARγ. 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.

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

86%

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

2000

vol. 47

issue 4

1147-1157

Peroxisome proliferator-activated receptors-γ (PPARγ) are ligand-inducible transcription factors of the nuclear hormone receptor superfamily. We examined the effect of PPARγ 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 PPARγ activators: prostaglandin J2 and ciglitazone. PPARγ were expressed in VSMC and RAW cells and their activity was upregulated in the presence of PGJ2 and ciglitazone. Incubation of the cells with PPARγ activators significantly augmented the release of VEGF protein into the media, both in resting and in IL-1β- 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 PPARγ upregulates the generation of VEGF and may be involved in the regulation of angiogenesis.

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2 Acta Biochimica Polonica

1 2003

1 2000

2 Dulak J.

1 Cisowski J.

1 Dembinska-Kiec A.

1 Huk I.

1 Jozkowicz A.

1 Józkowicz A.

1 Nigisch A.

1 Piatkowska E.

1 Placha W.

1 Weigel G.

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

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