title: Carvedilol improves left ventricular function in murine coxsackievirus-induced acute myocarditis association with reduced myocardial interleukin-1beta and MMP-8 expression and a modulated immune response.
abstract: 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.
  
  
  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-1beta, TNF-alpha, TGF-beta(1) 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-beta(1), IL-1beta 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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Department of Internal Medicine II, Cardiology and Pneumonology, Charité-University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany. pauschinger@ukbf.fu-berlin.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Pauschinger
authors.forename: Susanne
authors.initials: S
authors.lastname: Rutschow
authors.forename: Kumaran
authors.initials: K
authors.lastname: Chandrasekharan
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Anneke
authors.initials: A
authors.lastname: Weitz
authors.forename: Lothar
authors.initials: L
authors.lastname: Peter Schwimmbeck
authors.forename: Heinz
authors.initials: H
authors.lastname: Zeichhardt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poller
authors.forename: Michel
authors.initials: M
authors.lastname: Noutsias
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschope
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D003384:Coxsackievirus Infections / Q000503:physiopathology; D007375:Interleukin-1 / Q000378:metabolism*; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D011412:Propanolamines / Q000494:pharmacology*; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D007375:Interleukin-1; D011412:Propanolamines; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D000077261:Carvedilol; D020782:Matrix Metalloproteinases; D020784:Matrix Metalloproteinase 8; D008790:Metoprolol