Poster presentation. Abstract: Matrix metalloproteinase (MMP) plays a crucial role in vascular diseases and inflammatory mediator lipopolysaccharide (LPS) is a powerful stimulator of MMP expression. Thus, researchers have long sought to discover agents that are potent in inhibiting LPS-stimulated proinflammatory gene expression and useful to treat vascular diseases. In this study, we demonstrated that simvastatin, a 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, effectively inhibited LPS-stimulated MMP-1 as well as MMP-8 and MMP-9 expression by U937 mononuclear cells. Furthermore, results showed that geranylgeranyl transferase inhibitor (GGTI) inhibited LPS-stimulated MMP-1 expression and addition of isoprenoid intermediate geranylgeranyl pyrophosphate (GGPP) diminished the inhibitory effect of simvastatin on LPS-stimulated MMP-1 expression. Results also showed that simvastatin inhibited the membrane association of Ras and Rac and the inhibition was abolished by addition of GGPP. In addition, inhibition of Ras and Rac isoprenylation by Ras and Rac inhibitors led to inhibition of MMP-1 expression. These results indicate that Ras and Rac protein isoprenylation is targeted by simvastatin in the inhibition of LPS-stimulated MMP-1 expression. Moreover, we showed that simvastatin inhibited LPS-stimulated nuclear transcription factor AP-1, but not NFkB activity, and the inhibition was reversed by addition of GGPP. Simvastatin also inhibited LPS-stimulated extracellular signal-regulated kinase (ERK), but not p38 mitogen-activated protein kinase (MAPK) and Jun N-terminal kinase (JNK). Finally, we showed that the inhibitory effect of simvastatin on LPS-stimulated ERK activation was significantly reduced by addition of GGPP. Taken together, this study showed that simvastatin suppresses LPS-induced MMP-1 expression in U937 mononuclear cells by targeting Ras and Rac protein isoprenylation-mediated ERK activation.
This work was supported by NIH grant DE16353 and a Merit Review Grant from Department of Veterans Affairs (to Y.H.).Division of Endocrinology, Diabetes and Medical Genetics; Department of Medicine; Department of Biostatistics,Bioinformatics & Epidemiology; Division of Periodontics; Department of Stomatology; College of Medicine; College of Dental Medicine