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  • Title: Simvastatin inhibits TNFalpha-induced invasion of human cardiac myofibroblasts via both MMP-9-dependent and -independent mechanisms.
    Author: Turner NA, Aley PK, Hall KT, Warburton P, Galloway S, Midgley L, O'Regan DJ, Wood IC, Ball SG, Porter KE.
    Journal: J Mol Cell Cardiol; 2007 Aug; 43(2):168-76. PubMed ID: 17560598.
    Abstract:
    Statins can reduce adverse myocardial remodeling independently of their cholesterol-lowering ability. We have previously reported that simvastatin inhibits tumor necrosis factor-alpha (TNFalpha)-induced cardiac myofibroblast invasion and MMP-9 secretion, key events in this remodeling process. The aim of the present study was to investigate the mechanisms underlying this effect. Selective MMP-9 gene silencing with siRNA oligonucleotides revealed that myofibroblast invasion through a Matrigel barrier (Boyden chamber assay) was MMP-9-dependent. In contrast, cell migration (in the absence of Matrigel) was MMP-9-independent. Simvastatin, a commonly prescribed statin, inhibited both invasion and migration of myofibroblasts and disrupted the actin cytoskeleton as determined by confocal microscopy of rhodamine-phalloidin staining. All these effects of simvastatin were mimicked by the Rho-kinase inhibitor Y27632. TNFalpha activated the ERK-1/2, p38 MAPK, PI-3-kinase and NF-kappaB pathways but not the JNK pathway, as determined by immunoblotting with phospho-specific antibodies. Quantitative RT-PCR revealed that TNFalpha-induced MMP-9 mRNA expression was substantially reduced by pharmacological inhibitors of the ERK-1/2, PI-3-kinase and NF-kappaB pathways. However, none of the signal transduction pathways studied was influenced by simvastatin treatment. Moreover, despite reducing MMP-9 secretion, simvastatin had no effect on MMP-9 promoter activity (luciferase reporter assay) and actually increased MMP-9 mRNA levels. In summary, simvastatin reduces TNFalpha-induced invasion of human cardiac myofibroblasts through two distinct mechanisms: (i) by attenuating cell migration via Rho-kinase inhibition and subsequent cytoskeletal disruption, and (ii) by decreasing MMP-9 secretion via a post-transcriptional mechanism.
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