Pravastatin suppresses the interleukin-8 production induced by thrombin inhuman aortic endothelial cells cultured with high glucose by inhibiting the p44/42 mitogen activated protein kinase

1 3-Hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors (statins) pre vent the progression of atherosclerosis by lowering cholesterol. However, t he effect of statins on the synthesis of proinflammatory cytokines from end othelial cells has not yet been fully investigated. Here, we examined the e ffect of pravastatin one of the statins, on IL-8 synthesis induced by throm bin in human aortic endothelial cells (AoEC) cultured with high glucose con centrations. 2 Pravastatin significantly decreased the IL-8 synthesis induced by thrombi n. 3 Pravastatin inhibited the p44/42 MAP kinase activity induced by thrombin, but did not inhibit the p38 MAP kinase activity. 4 Translocation of ras protein from the cytosol to plasma membrane was inhi bited by pravastatin. 5 Pravastatin inhibit the activator protein-1 activity, but did not inhibit the activation or I kappaB-alpha. 6 Dominant negative ras inhibited the p44/42 MAP kinase activity induced by PMA. 7 Our results suggest that pravastatin inhibits IL-8 synthesis by blocking the ras-MAP (p44/42) kinase pathway rather than nuclear factor-kappaB. Prav astatin may prevent atherosclerosis not only by lowering cholesterol levels , but also by suppressing IL-8 synthesis in AoEC through the inhibition of p44/42 MAP kinase, and this may be more beneficial in diabetic patients tha n in non-diabetics.