Exp Mol Med.
2009 Apr;41(4):277-287. 10.3858/emm.2009.41.4.031.
Simvastatin inhibits induction of matrix metalloproteinase-9 in rat alveolar macrophages exposed to cigarette smoke extract
- Affiliations
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- 1Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Korea. yslee@skku.edu
- 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine Pochon CHA University, Seongnam, Korea.
- 3Department of Laboratory Medicine College of Medicine, Seoul National University Seoul, Korea.
- 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Clinical Research Center for Chronic Obstructive Airway Diseases, Seoul, Korea.
- KMID: 1088603
- DOI: http://doi.org/10.3858/emm.2009.41.4.031
Abstract
- Matrix metalloproteinase-9 (MMP-9) may play an important role in emphysematous change in chronic obstructive pulmonary disease (COPD), one of the leading causes of mortality and morbidity worldwide. We previously reported that simvastatin, an inhibitor of HMG-CoA reductase, attenuates emphysematous change and MMP-9 induction in the lungs of rats exposed to cigarette smoke. However, it remained uncertain how cigarette smoke induced MMP-9 and how simvastatin inhibited cigarette smoke-induced MMP-9 expression in alveolar macrophages (AMs), a major source of MMP-9 in the lungs of COPD patients. Presently, we examined the related signaling for MMP-9 induction and the inhibitory mechanism of simvastatin on MMP-9 induction in AMs exposed to cigarette smoke extract (CSE). In isolated rat AMs, CSE induced MMP-9 expression and phosphorylation of ERK and Akt. A chemical inhibitor of MEK1/2 or PI3K reduced phosphorylation of ERK or Akt, respectively, and also inhibited CSE-mediated MMP-9 induction. Simvastatin reduced CSE-mediated MMP-9 induction, and simvastatin-mediated inhibition was reversed by farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP). Similar to simvastatin, inhibition of FPP transferase or GGPP transferase suppressed CSE-mediated MMP-9 induction. Simvastatin attenuated CSE-mediated activation of RAS and phosphorylation of ERK, Akt, p65, IkappaB, and nuclear AP-1 or NF-kappaB activity. Taken together, these results suggest that simvastatin may inhibit CSE-mediated MMP-9 induction, primarily by blocking prenylation of RAS in the signaling pathways, in which Raf-MEK-ERK, PI3K/Akt, AP-1, and IkappaB-NF-kappaB are involved.
Keyword
MeSH Terms
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1-Phosphatidylinositol 3-Kinase/metabolism
Alkyl and Aryl Transferases/metabolism
Animals
Anticholesteremic Agents/pharmacology
Cells, Cultured
Enzyme Inhibitors/metabolism/pharmacology
Extracellular Signal-Regulated MAP Kinases/metabolism
Gene Expression Regulation, Enzymologic/*drug effects
I-kappa B Kinase/antagonists & inhibitors/metabolism
Macrophages, Alveolar/cytology/*drug effects/*enzymology
Matrix Metalloproteinase 9/genetics/*metabolism
Mitogen-Activated Protein Kinase Kinases/metabolism
Polyisoprenyl Phosphates/metabolism
Proto-Oncogene Proteins c-akt/metabolism
Rats
Sesquiterpenes/metabolism
Signal Transduction/physiology
Simvastatin/*pharmacology
Smoke/*adverse effects
*Tobacco/adverse effects/chemistry
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