© 2005 European Society of Cardiology
Carvedilol improves left ventricular function in murine coxsackievirus-induced acute myocarditis Association with reduced myocardial interleukin-1β and MMP-8 expression and a modulated immune response
a Department of Internal Medicine II, Cardiology and Pneumonology, Charité-University Medicine Berlin, Campus Benjamin Franklin Hindenburgdamm 30, D-12200 Berlin, Germany
b Institute for Infectious Diseases Medicine, Charité-University Medicine Berlin, Campus Benjamin Franklin Hindenburgdamm 30, D-12200 Berlin, Germany
c Institute for Pharmacology and Toxicology, Charité-University Medicine Berlin Campus Mitte, Berlin
* Corresponding author. Tel.: +49 30 8445 2349; Fax: +49 30 8445 4648.E-mail address: pauschinger{at}ukbf.fu-berlin.de
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Abstract |
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Background: Proinflammatory cytokines induce the expression of matrix metalloproteinases that play a crucial role in myocardial remodeling. Beta-adrenergic receptor stimulation influences the production of cytokines heralding the possibility of modulating cytokine production by beta-adrenergic blockers.
Methods and results: In a coxsackievirus B3 murine myocarditis model (BALB/c), effects of carvedilol and metoprolol on myocardial cytokine expression, inflammatory cell infiltration and MMP/TIMP profiles were investigated. In carvedilol-treated mice, a significant improvement in left ventricular function was documented 10 days post infection. In infected mice (n=10), IL-1β, TNF-
, TGF-β1 and IL-10 myocardial mRNA abundance were increased significantly (240%, 200%, 161%, and 230%) compared to controls (n=10), while IL-15 mRNA was markedly reduced (70%). Infected mice showed significantly increased infiltrations with CD3-, CD4- and CD8-T-lymphocytes (730%, 1110%, 380%). In the infected mice, myocardial MMP/TIMP profiles presented a significant upregulation of membrane type-1 MMP, MMP-9, MMP-8 and MMP-3 (150%, 160%, 340%, and 270%) and a significant decrease in TIMP-4 levels (75%). Carvedilol attenuated over-expression of myocardial TGF-β1, IL-1β and MMP-8 mRNA expression significantly and induced a relevant IL-10 mRNA expression in the infected mice (n=10). By an unchanged infiltration with CD3-T-lymphocytes, carvedilol showed a representative reduction in CD4-T-lymphocytes.
Conclusion: Carvedilol treatment in experimental myocarditis leads to reduced expression of proinflammatory cytokines and MMPs, which contributes to reduced matrix degradation and ultimately to improved structural integrity of the heart. Besides the antiadrenergic potential, carvedilol is beneficial due to a wide range of biological activities (antiinflammatory, antifibrotic, antioxidative and immunomodulatory).
Key Words: Carvedilol • Metoprolol • TGF-β1 • Interleukin-1β • Myocarditis • Matrix metalloproteinase
Received November 7, 2003; Revised May 17, 2004; Accepted July 5, 2004
1 The first two authors contributed equally to this work.
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