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Thromb Haemost 2000; 84(04): 706-711
DOI: 10.1055/s-0037-1614091
Review Article
Schattauer GmbH

In Vivo Stimulation of Vascular Plasminogen Activator Inhibitor-1 Production by very Low-Density Lipoprotein Involves Transcription Factor Binding to a VLDL-Responsive Element

Wolfgang Dichtl
1   From the Wallenberg Laboratory, Department of Medicine, Malmö University Hospital, Lund University, Sweden
2   King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden
3   Department of Medicine, Division of Cardiology, University Hospital of Innsbruck, Austria; and
,
Mikko P. S. Ares
1   From the Wallenberg Laboratory, Department of Medicine, Malmö University Hospital, Lund University, Sweden
,
Maria Stollenwerk
1   From the Wallenberg Laboratory, Department of Medicine, Malmö University Hospital, Lund University, Sweden
,
Cecilia M. Giachelli
4   Department of Pathology, University of Washington, Seattle, USA
,
Marta Scatena
4   Department of Pathology, University of Washington, Seattle, USA
,
Anders Hamsten
2   King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden
,
Per Eriksson
2   King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden
,
Jan Nilsson
1   From the Wallenberg Laboratory, Department of Medicine, Malmö University Hospital, Lund University, Sweden
› Author AffiliationsThis study was supported by grants from the Swedish Medical Research Council (8311 and 8691), the Swedish Heart-Lung Foundation, the Marianne and Marcus Wallenberg Foundation, the King Gustaf V 80th Birthday Foundation, the Petrus and Augusta Hedlund Foundation, the Foundation For Old Servants, the Professor Nanna Svartz Foundation and the King Gustaf V and Queen Victoria Foundation. P.E. is supported by a postdoctoral research fellowship from the Swedish Medical Research Council. The support of Prof. Otmar Pachinger (Department of Medicine, Division of Cardiology, University Hospital of Innsbruck, Austria) during the completion of this work was much appreciated.
Further Information

Publication History

Received 17 December 1999

Accepted after resubmission 12 May 2000

Publication Date:
11 December 2017 (online)

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Summary

High plasma levels of plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of cardiovascular disease. There is also a close relation between high plasma levels of PAI-1 and hypertriglyceridemia. Cell culture studies have shown that very low density lipoprotein (VLDL) increases the production and secretion of PAI-1 in endothelial cells and hepatocytes, suggesting a possible mechanism for this association. To determine whether VLDL stimulates PAI-1 production in vascular cells also in vivo, Sprague-Dawley rats were injected intravenously with 6 mg/kg of VLDL (derived from human subjects with type IV hyperlipidemia). Previous studies have demonstrated that this results in an accumulation of human VLDL in the aorta and other arteries followed by increased nuclear factor-kappa B (NF-κB) activation. Endothelial, but not smooth muscle cells, showed a basal PAI-1 mRNA and protein expression as assessed by in situ hybridization and immunohistochemistry, respectively. Six to twenty-four hours after the VLDL injection, lipoprotein particle accumulation was seen in the aortic wall, which was accompanied by increasing PAI-1 mRNA and protein expression in endothelial and smooth muscle cells. Within the rat PAI-1 promoter we identified a sequence located at −589 to −571 with 74% homology with the recently described VLDL responsive element in the human PAI-1 promoter and located adjacent to a 4-guanosine motif presumably corresponding to the human 4G/5G polymorphism. Transient transfection studies showed that VLDL exerts its stimulatory effects on rat PAI-1 gene expression in vascular cells by interaction with promoter sequences located within bp −656 and −505. Electrophoretic mobility shift assays showed that VLDL increases the binding of as yet incompletely characterized factors to this response element. Taken together these observations support a direct influence of VLDL on vascular PAI-1 gene expression in vivo. This stimulation is exerted on the level of PAI-1 gene transcription, and involves transcription factor binding to a VLDL responsive element adjacent to a 4G motif within the PAI-1 promoter.

Key words

Hypertriglyceridemia - plasminogen activator inhibitor-1 - VLDL-RE - NF-κB-like proteins
 

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