S-Space College of Medicine/School of Medicine (의과대학/대학원) Laboratory Medicine (검사의학전공) Journal Papers (저널논문_검사의학전공)
Simvastatin inhibits induction of matrix metalloproteinase-9 in rat alveolar macrophages exposed to cigarette smoke extract
- Kim, Sang-Eun; Thuy, Tran Thi Thanh; Lee, Ji-Hyun; Ro, Jai Youl; Kong, Yoon; Lee, Dong-Soon; Lee, Sang-Do; Lee, Yun-Song; Oh, Yeon-Mock; Ahn, Jee-Yin; Bae, Young-An
- Issue Date
- EXPERIMENTAL AND MOLECULAR MEDICINE; Vol.41 4; 277-287
- macrophages, alveolar; matrix metalloproteinases-9; simvastatin; pulmonary emphysema; pulmonary disease, chronic obstructive; smoking
- 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, I kappa B, and nuclear AP-1 or NF-kappa B 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 I kappa B-NF-kappa B are involved.