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Enhancement by Homocysteine of Plasminogen Activator Inhibitor-1 Gene Expression and Secretion from Vascular Endothelial and Smooth Muscle Cells

https://doi.org/10.1006/bbrc.2000.2753Get rights and content

Abstract

In order to elucidate the relationship between homocysteine and the fibrinolytic system, we examined the effect of homocysteine on plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) gene expression and protein secretion in cultured human vascular endothelial and smooth muscle cells in vitro. PAI-1 mRNA and secreted protein levels were both enhanced by homocysteine in a dose dependent manner, with significant stimulation of PAI-1 secretion observed at concentrations greater than 0.5 mM homocysteine. In contrast, secretion and mRNA expression of tPA were not significantly altered by homocysteine stimulation. Secretion of TGFβ (transforming growth factor β) and TNFα (tumor necrosis factor α), possible regulators of PAI-1 expression and secretion, were not stimulated by treatment with 1.0 mM homocysteine. These results suggests that hyperhomocysteinemia-induced atherosclerosis and/or thrombosis may be caused by homocysteine-induced stimulation of PAI-1 gene expression and secretion in the vasuculatures by a mechanism independent from paracrine-autocrine activity of TGFβ and TNFα.

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    Abbreviations used: PAI-1, plasminogen activator inhibitor-1; tPA, tissue type plasminogen activator; TGFβ, transforming growth factor β; TNFα, tumor necrosis factor α; MTHFR, methylene tetrahydro-folate reductase; HUVEC, human umbilical vascular endothelial cells; HASMC, human aorta smooth muscle cells.

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