Inhibition of Rho/Rho-kinase signaling downregulates plasminogen activator inhibitor-1 synthesis in cultured human monocytes.
Biochim Biophys Acta
; 1590(1-3): 123-30, 2002 Jun 12.
Article
en En
| MEDLINE
| ID: mdl-12063175
ABSTRACT
Increased production of plasminogen activator inhibitor-1 (PAI-1) in plaques plays a role in the pathogenesis of atherosclerosis. This study was conducted to investigate the effect of blockade of Rho/Rho-kinase signaling on the synthesis of PAI-1 in cultured human peripheral blood monocytes. HMG-CoA reductase inhibitors (statins) and inhibitors of Rho and Rho-kinase were added to monocyte cultures. The levels of PAI antigen and mRNA were determined by Western blotting and RT-PCR, respectively, and PAI-1 expression was assessed by immunohistochemistry. We performed pull-down assays to determine the activity of Rho by measuring the GTP-bound form of Rho A. In unstimulated and lipopolysaccharide (LPS)-stimulated cultured monocytes, statins reduced the levels of PAI-1 antigen and mRNA. The suppressive effects of statins on PAI-1 synthesis were reversed by geranylgeranylpyrophosphate (GGPP) and were mimicked by C3 exoenzyme. Immunohistochemistry confirmed the role of lipid modification by GGPP in suppressive effect of statins in PAI-1 synthesis. Pull-down assays demonstrated that statins decreased the levels of the GTP-bound form of Rho A. Our findings suggest that statins decrease the activity of Rho by inhibiting geranylgeranylation. Moreover, Rho-kinase inhibitors, Y-27632 and fasudil, suppressed the synthesis of PAI-1 in this culture system. We show that inhibition of Rho/Rho-kinase signaling downregulates the synthesis of PAI-1 in human monocytes.
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Bases de datos:
MEDLINE
Asunto principal:
Toxinas Botulínicas
/
Monocitos
/
Proteínas Serina-Treonina Quinasas
/
Inhibidor 1 de Activador Plasminogénico
/
1-(5-Isoquinolinesulfonil)-2-Metilpiperazina
/
Proteínas de Unión al GTP rho
Tipo de estudio:
Etiology_studies
Límite:
Humans
Idioma:
En
Revista:
Biochim Biophys Acta
Año:
2002
Tipo del documento:
Article
País de afiliación:
Japón