Statins suppress THP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibiting geranylgeranylation.
Macrophages secrete matrix metalloproteinase 9 (MMP-9), an enzyme that weakens the fibrous cap of atherosclerotic plaques, predisposing them to plaque rupture and subsequent ischemic events. Recent work indicates that statins strongly reduce the possibility of heart attack. Furthermore, these compounds appear to exert beneficial effects not only by lowering plasma low-density-lipoprotein cholesterol but also by directly affecting the artery wall. To evaluate whether statins influence the proinflammatory responses of monocytic cells, we studied their effects on the chemotactic migration and MMP-9 secretion of human monocytic cell line THP-1. Simvastatin dose dependently inhibited THP-1 cell migration mediated by monocyte chemoattractant protein 1, with a 50% inhibitory concentration of about 50 nM. It also inhibited bacterial lipopolysaccharide-stimulated secretion of MMP-9. The effects of simvastatin were completely reversed by mevalonate and its derivatives, farnesylpyrophosphate and geranylgeranyl pyrophosphate, but not by ubiquinone. Additional studies revealed similar but more profound inhibitory effects with L-839,867, a specific inhibitor of geranylgeranyl transferase. However, alpha-hydroxyfarnesyl phosphonic acid, an inhibitor of farnesyl transferase, had no effect. C3 exoenzyme, a specific inhibitor of the prenylated small signaling Rho proteins, mimicked the inhibitory effects of simvastatin and L-839,867. These data supported the role of geranylgeranylation in the migration and MMP-9 secretion of monocytes.
Wong
B
B
Departments of. Lipid Biochemistry, Merck Research Laboratories, Rahway, New Jersey, USA.
Lumma
W C
WC
Smith
A M
AM
Sisko
J T
JT
Wright
S D
SD
Cai
T Q
TQ
D036002:ADP Ribose Transferases / Q000494:pharmacology; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001905:Botulinum Toxins; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007948:Leukemia, Monocytic, Acute / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008798:Mevalonic Acid / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009930:Organic Chemicals; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012717:Sesquiterpenes; D019821:Simvastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C431699:L 839867; D008070:Lipopolysaccharides; D009363:Neoplasm Proteins; D009930:Organic Chemicals; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D019821:Simvastatin; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D020780:Matrix Metalloproteinase 9; D001905:Botulinum Toxins; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid