Statins suppress glucose-induced plasminogen activator inhibitor-1 expression by regulating RhoA and nuclear factor-κB activities in cardiac microvascular endothelial cells

The aim of this study was to investigate the possible proinflammatory signaling pathways involved in statin inhibition of glucose-induced plasminogen activator inhibitor-1 (PAI-1) expression in cardiac microvascular endothelial cells (CMECs). Primary rat CMECs were grown in the presence of 5.7 or 23 mmol/L glucose. PAI-1 mRNA and protein expression levels were measured by realtime polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay, respectively. A pull-down assay was performed to determine RhoA activity. I kappa B alpha protein expression was measured by Western blotting, nuclear factor (NF)-kappa B activation was detected by electrophoretic mobility shift assay and its transcription activity was determined by a dual luciferase reporter gene assay. PAI-1 mRNA and protein expression levels were both increased with high glucose concentrations, but they were significantly suppressed by simvastatin and atorvastatin treatment (P < 0.01) and the effects were reversed by mevalonate (100 mu mol/L) and geranylgeranyl pyrophosphate (10 mu mol/L) but not farnesyl pyrophosphate (10 mu mol/L). Such effects were similar to those of a RhoA inhibitor, C-3 exoenzyme (5 mu g/mL), inhibitors of RhoA kinase (ROCK), Y-27632 (10 mu mol/L) and hydroxyfasudil (10 mu mol/L) and an NF-kappa B inhibitor, BAY 11-7082 (5 mu mol/L). High glucose-induced RhoA and NF-kappa B activations in CMECs were both significantly inhibited by statins (P < 0.01). Simvastatin and atorvastatin equally suppress high glucose-induced PAI-1 expression. These effects of statins may occur partly by regulating the RhoA/ROCK NF-kappa B pathway. The multifunctional roles of statins may be particularly beneficial for patients with metabolic syndrome.