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Ishibashi, T. et al.

Inhibition of Rho/Rho-kinase signaling downregulates plasminogen activator inhibitor-1 synthesis in cultured human monocytes.

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.[1]

References

Inhibition of Rho/Rho-kinase signaling downregulates plasminogen activator inhibitor-1 synthesis in cultured human monocytes. Ishibashi, T., Nagata, K., Ohkawara, H., Sakamoto, T., Yokoyama, K., Shindo, J., Sugimoto, K., Sakurada, S., Takuwa, Y., Teramoto, T., Maruyama, Y. Biochim. Biophys. Acta (2002) [Pubmed]

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