Simvastatin inhibits induction of matrix metalloproteinase-9 in rat alveolar macrophages exposed to cigarette smoke extract

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.

Changes in the isoprenoid pathway in syndrome X.

This study assessed the changes in digoxin and some other metabolites of the isoprenoid pathway in metabolic syndrome X presenting with multiple lacunar state. There was an increase in plasma HMG CoA reductase activity with a consequent increase in serum digoxin, which caused a reduction in RBC membrane Na+-K+ ATPase activity. There was an increase in serum tryptophan and its metabolites and a decrease in tyrosine and its metabolites. Serum magnesium was decreased with consequent alteration in the metabolism of glycosaminoglycans and glycolipids. Increase in dolichol, another product of the isoprenoid pathway resulted in alteration in glycoprotein metabolism. Changes in the composition of membrane glycosaminoglycans, glycoproteins and cholesterol:phospholipid ratio were also observed in this disorder leading to decreased lysosomal stability. Decrease in ubiquinone, another isoprenoid metabolite resulted in alteration in the free radical generation. Membrane Na+-K+ ATPase inhibition due to digoxin, altered membrane structure, increased tryptophan catabolites and decreased tyrosine catabolites can lead on to increased intracellular calcium and reduced intracellular magnesium which can account for the symptoms of syndrome X.