Journal
CARDIOVASCULAR RESEARCH
Volume 64, Issue 3, Pages 507-515Publisher
OXFORD UNIV PRESS
DOI: 10.1016/j.cardiores.2004.07.020
Keywords
tumor necrosis factor alpha; human atrial myofibroblast; MMP-9
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Objective: Tumor necrosis factor alpha (TNFalpha) is implicated in myocardial remodeling, a process in which activated cardiac fibroblasts (myofibroblasts) secrete matrix-degrading metal loprotemases (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 TNFalpha 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. TNFalpha (1 ng/ml) induced a 23.1 +/- 3.9% increase in cell number after 4 days (P<0.001). Additionally, TNFalpha (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 TNFalpha were predominantly TNF-RI-mediated. Simvastatin (0.1-10 mumol/l) concentration dependently inhibited TNFalpha-induced myofibroblast proliferation, invasion and MMP-9 secretion. Conclusions: TNFalpha acting predominantly via the TNF-RI 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. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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