Simvastatin Inhibits Tnfalpha-induced Invasion of Human Cardiac Myofibroblasts Via Both Mmp-9-dependent and -independent Mechanisms.
From: Academic Unit of Cardiovascular Medicine, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK.
Journal of molecular and cellular cardiology
- Publish Date: Aug 2007
- ISSN: 0022-2828
- Volume: 43
- Issue: 2
- Pages: 168-76
- Medium: Print
- Language: English
- Citation (JAMA): Turner Neil A, Aley Parvinder K, Hall Kersten T, et al. Simvastatin Inhibits Tnfalpha-induced Invasion of Human Cardiac Myofibroblasts Via Both Mmp-9-dependent and -independent Mechanisms.. J. Mol. Cell. Cardiol. Aug 2007;43:168-76
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.
Mesh Headings (Keywords): Actins, Amides, Cell Movement, Cells, Cultured, Cytoskeleton, Fibroblasts, Gene Expression Regulation, Enzymologic, Gene Silencing, Humans, Intracellular Signaling Peptides and Proteins, Matrix Metalloproteinase 9, Myocardium, Promoter Regions (Genetics), Protein-Serine-Threonine Kinases, Pyridines, RNA, Messenger, Signal Transduction, Simvastatin, Transcription, Genetic, Tumor Necrosis Factor-alpha, rho-Associated Kinases
Check for Full Text / PubMed Unique Identifier (PMID): 17560598
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