© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Tumor necrosis factor 
induces human atrial myofibroblast proliferation, invasion and MMP-9 secretion: inhibition by simvastatin
aInstitute for Cardiovascular Research, Academic Unit for Cardiovascular Medicine, Worsley Building, University of Leeds, Leeds LS2 9JT, UK
bDepartment of Cardiac Surgery, The Yorkshire Heart Centre, Leeds General Infirmary, Leeds LS1 3EX, UK
* Corresponding author. Tel.: +44 113 3434807; fax: +44 113 3434803. Email address: medkep{at}leeds.ac.uk
Objective: Tumor necrosis factor 
(TNF) is implicated in myocardial remodeling, a process in which activated cardiac fibroblasts (myofibroblasts) secrete matrix-degrading metalloproteinases (MMPs) and undergo increased proliferation and invasion. Statins are cholesterol-lowering drugs that also have direct cellular effects, which may underlie their ability to reduce myocardial remodeling. This study investigated the effect of TNF on human cardiac myofibroblast proliferation, invasion and MMP-9 secretion, and determined whether these properties were modulated by simvastatin.
Methods: Human cardiac myofibroblasts were cultured from right atrial appendage. TNF receptor expression was quantified by immunoblotting. Cell proliferation, invasion, MMP-9 secretion and MMP-9 mRNA expression were determined by cell counting, Matrigel-coated modified Boyden chamber assays, gelatin zymography and RT-PCR, respectively.
Results: Human atrial myofibroblasts expressed the TNF-RI and TNF-RII receptor subtypes. TNF (1 ng/ml) induced a 23.1±3.9% increase in cell number after 4 days (P<0.001). Additionally, TNF (1–10 ng/ml) significantly (P<0.01) increased myofibroblast invasion, with a concomitant increase in MMP-9 secretion, that was due to increased MMP-9 mRNA levels. Using TNF-R-specific neutralizing antibodies, we determined that these cellular effects of TNF were predominantly TNF-RI-mediated. Simvastatin (0.1–10 µmol/l) concentration dependently inhibited TNF-induced myofibroblast proliferation, invasion and MMP-9 secretion.
Conclusions: TNF, acting predominantly via the TNF-R1 receptor, increased human atrial myofibroblast proliferation, invasion and MMP-9 secretion, all of which were inhibited by simvastatin. Inhibition of cytokine-induced cardiac myofibroblast activation by statins provides a rationale for their use in patients with cardiac pathologies characterized by adverse myocardial remodeling.
KEYWORDS Tumor necrosis factor ; Human atrial myofibroblast; MMP-9
Time for primary review 28 days
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