Skip Navigation

European Journal of Heart Failure 2005 7(4):444-452; doi:10.1016/j.ejheart.2004.07.002
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Pauschinger, M.
Right arrow Articles by Tschope, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pauschinger, M.
Right arrow Articles by Tschope, C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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

Matthias Pauschingera,*,1, Susanne Rutschowa,1, Kumaran Chandrasekharana, Dirk Westermanna, Anneke Weitza, Lothar Peter Schwimmbecka, Heinz Zeichhardtb, Wolfgang Pollera, Michel Noutsiasa, Jun Lic, Heinz-Peter Schultheissa and Carsten Tschopea

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


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
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-{alpha}, 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. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Viral myocarditis is a common cause of acute heart failure, especially in young patients [1]. Viral infection of the myocardium and the ensuing inflammatory reaction constitute the major pathogenic mechanisms, which ultimately lead to left ventricular dysfunction [2].

The balance between the protective and deleterious immune mechanisms may eventually determine the course of the disease [3].

Cytokines play a critical role in maintaining this balance as they are known to modulate lymphocyte and myocardial cell functions [4,5]. Since proinflammatory cytokines promote myocyte hypertrophy in vitro [6] and regulate cardiac fibroblast function [7] including expression of extracellular matrix components like collagen type I, type III, and fibronectin, they also play an important role in left ventricular remodeling. Proinflammatory cytokines disturb the balance between matrix metalloproteinases (MMPs), a family of zinc-dependent proteases which degrade various extracellular matrix proteins and their derivative peptides and tissue inhibitors of MMPs (TIMPs) [8,9], thereby contributing to development of left ventricular dysfunction [8,10]. Immunomodulation, by targeting the cytokines, can influence prognosis. Interleukin-2 (IL-2) treatment in a murine model of viral myocarditis aggravated myocardial inflammation and the severity of disease [11]. Recently, local expression of interleukin-1 (IL-1) receptor antagonist was found to improve mortality and decrease myocardial inflammation in experimental coxsackieviral myocarditis [12].

Carvedilol is a non-selective β-blocker with additional properties including {alpha}1-adrenergic-blockade, antioxidative effects, and antifibrotic properties, which may facilitate the overall clinical benefit observed in heart failure. Moreover, carvedilol improves ventricular function, reduces ventricular dilatation, and improves survival in patients with left ventricular dysfunction [13]. Carvedilol improves left ventricular function in dilated cardiomyopathy patients [14] and alters myocardial gene expression in post-myocardial ischemia [15] by influencing the circulating levels of cytokines (IL-6, TNF-{alpha} and IL-1β). These findings are important, since cytokines are associated with progressive heart failure, in parts due to negative inotropic effects [16].

However, the precise mechanisms of the beneficial effects of carvedilol, especially the possible influence on the remodeling of the extracellular matrix (ECM), are still elusive. In the present study, we compared the effects of carvedilol and metoprolol treatment in a murine model of acute viral myocarditis, on left ventricular function and myocardial gene expression profiles, focusing on extracellular matrix remodeling (ECM-components, MMPs and TIMPs) and the myocardial expression of cytokines.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Murine viral myocarditis
Specific pathogen-free inbred, 8-week-old, male Balb/c (H-2d) mice obtained from Robert von Ostertag Institute, Berlin, Germany, were used for the experiments described in this study (n=60). Animals were infected as described previously (n=30) [17]. Briefly, 5x105 plaque forming units (p.f.u.) of coxsackievirus B3 (Strain Nancy, ATCC VR-30) were diluted in phosphate-buffered saline to a final volume of 0.2 ml and injected intraperitoneally. Sham-infected animals (0.2 ml PBS intraperitoneally) were used as control (n=30). Suitable controls and infected animals were maintained and sacrificed in accordance with German Animal Protection Law 1993.

2.2. Drug administration
Carvedilol (5 mg/kg/12 h) and metoprolol (15 mg/kg/12 h) were administered orally (5 mg/kg/12 h) for 9 days, starting 24 h after infection (n=20) and sham infection (n=20) [18].

2.3. Hemodynamic characterization of LV function
Ten days after infection, hemodynamic parameters were measured in anesthetized, artificially ventilated and closed-chest animals. Due to the invasive procedure, the hemodynamic parameters were analyzed in a subgroup of animals; controls n=8, controls/carvedilol n=7, controls/metoprolol n=8, infected n=6, infected/carvedilol n=9, infected/metoprolol n=6. Left ventricular pressure (LVP), maximal rate of pressure increase over time (dP/dtmax) as a parameter of left ventricular (LV) contractility, the minimal rate of pressure decrease over time (dP/dtmin) as an indicator of the LV relaxation and heart rate were determined via a 1.2 F Milar-Tip catheter introduced into the LV chamber. Immediately after the hemodynamic parameters were obtained, the hearts were rapidly removed and transversely dissected.

2.4. RNA isolation and reverse transcription
Following hemodynamic evaluation, mice were sacrificed and the myocardial tissue was collected for different measurements. Total RNA, frozen in liquid nitrogen, was extracted from the myocardial samples by the Trizol method (GIBCO BRL) as per the manufacturer's instructions. Following treatment with RNase-free DNase I (Roche, Mannheim, Germany), the reverse transcription was performed using first-strand cDNA synthesis kit (Promega, Mannheim, Germany) [17].

2.5. Enteroviral RNA detection
Nested polymerase chain reaction was employed with the reverse transcripted RNA to detect the presence of viral genome in the infected myocardium as described earlier [17].

2.6. Reverse transcriptase-polymerase chain reaction
Semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the mRNA abundance of MMP-3, MMP-8, MMP-9, MT-1MMP, EMMPRIN (extracellular-MMP-inducer), TIMP-4, IL-1β, TGF-β1 TNF-{alpha}, IL-10, IL-15, collagen type I (Col I), collagen type III (Col III), and fibronectin, based on the methods described earlier (Table 1) [17]. Additionally, RT-PCR was also used to detect the CVB-3 RNA abundance in the infected myocardium. The mRNA abundance was quantified as optical densities (OD) equalized with β-actin mRNA levels using a software program (Scion Image. Maryland, USA). Nucleic acid sequences of all PCR products were confirmed to be identical to published GenBank data.


View this table:
[in this window]
[in a new window]

  		Table 1 Primer sequences used for semi-quantitative RT-PCR

 
2.7. Immunohistochemistry
Immunohistochemical analysis was performed as described earlier [17]. To analyze T-lymphocyte infiltration, we used rat anti-mouse-CD4 antibody (Pharmingen 1:50), rat anti-mouse-CD8a antibody (Pharmingen 1:50) and goat anti-mouse-CD3 antibody (Santa Cruz 1:25). Biotinylated rabbit anti-rat IgG (Dako 1:100) and biotinylated rabbit anti-goat IgG (Vector 1:200) were used as secondary antibodies and VECTASTAIN® (Vector) as ABC-reagent, respectively. Immunocompetent infiltrates were quantified by digital image analysis as described in detail elsewhere [19].

2.8. Statistical analysis
All data are expressed as mean±S.E. Statistical significance between multiple groups was determined using Kruskal–Wallis test followed by Mann–Whitney U-test. Values of P<0.05 were considered as significant. Correlations between two parameters were performed using Pearson's correlation. Values of r2<0.5 were considered as significant.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Hemodynamics of CVB3-infected mice
Coxsackievirus infection caused left ventricular dysfunction at 10 days post-infection. This was evidenced by significantly reduced left ventricular pressure (LVP), dP/dtmax, dP/dtmin and heart rate (HR) (Fig. 1a–c). This impairment of left ventricular function was significantly improved with carvedilol treatment for all parameters. Moreover, metoprolol treatment only produced a significant improvement in LV-contractility.


Figure 1
View larger version (33K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Left ventricular function on day 10 after coxsackievirus B3 (CVB3) infection in BALB/c (H-2d) mice, measured by heart rate (a), dP/dtmax and dP/dtmin (b) and LVP (c). Data are expressed as Mean±S.E. and P<0.05 were considered significant.

 
3.2. Presence of viral genome in the myocardium
Nested PCR analysis confirmed the presence of the viral genome in the myocardium of infected mice. In contrast, all sham-infected myocards were virus negative. Additionally, semiquantitative RT-PCR-analysis showed a significantly higher CVB-3-RNA abundance (240%, P<0.001) in the infected myocardium treated with carvedilol compared to the infected animals (Fig. 2).


Figure 2
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 CVB-3 RNA abundance in the infected myocardium of mice on day 10 post-infection in response to carvedilol and metoprolol administration measured by semi-quantitative RT-PCR.

 
3.3. Myocardial cytokine profiles
In the myocardium of the infected mice semiquantitative RT-PCR revealed a significant up-regulation of the mRNA abundances of IL-1β by 240% (P<0.0001), TNF-{alpha} by 200% (P<0.001) TGF-β1 by 160% (P<0.001) and IL-10 by 230% (P<0.002) compared to controls (Fig. 3a). In addition, cardiac IL-15 levels were significantly down-regulated by 70% (P<0.023). In the infected mice, carvedilol administration attenuated the increase in IL-1β and TGF-β1 significantly (p<0.05), while IL-10 levels were relevantly increased in the uninfected mice and the infected mice. Furthermore, carvedilol treatment maintained the baseline levels of IL-15 in the infected group. Metoprolol treatment had no effect on the myocardial cytokine profile.


Figure 3
View larger version (31K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Expression of cytokine mRNAs (a), MMP/TIMP mRNAs (b) and ECM-protein mRNAs (c) in the myocardial tissues of mice on day 10 after coxsackievirus B3 (CVB3) infection in response to carvedilol and metoprolol treatment.

 
3.4. Myocardial MMP/TIMP profiles
Fig. 3b illustrates the myocardial MMP/TIMP profiles in the experimental animals. mRNA analysis of the infected myocardium showed a significant increase in EMMPRIN by 130%, MT-1MMP by 150%, MMP-9 by 160%, MMP-3 by 270%, and MMP-8 by 340% (P<0.01, P<0.0001, P<0.019, P<0.0001, P<0.01, respectively). TIMP-4 was down-regulated to 75% (P<0.04). In the carvedilol-treated myocarditic mice, the MMP-8 mRNA abundance was significantly reduced with a trend to a reduction in the MMP-3 and the MMP-9 mRNA abundance. The mRNA abundance of MT-1MMP and TIMP-4 was unaffected. In contrast, the mRNA abundance of the MMP/TIMP-system was not influenced by metoprolol treatment.

3.5. Myocardial ECM-component profiles
In line with our previous report [17], mRNA analysis of the infected myocardium did not reveal any significant changes in the levels of fibronectin, collagen type I, and collagen type III (Fig. 3c). Carvedilol treatment produced a significant reduction in collagen type I and collagen type III mRNA abundance in the uninfected mice as well as collagen type I in the infected mice (P<0.05). However, treatment with metoprolol showed a significant reduction of fibronectin in the uninfected mice, with no effect on myocardial collagen levels.

3.6. Myocardial T-lymphocyte infiltration
The infected mice showed a significant infiltration of the CD3+, CD4+ and CD8+ T-lymphocytes (P<0.05; Fig 4). In addition, carvedilol treatment produced a relevant reduction in CD4+ T-lymphocytes in parallel with an induction of the CD8+ T-lymphocytes. However, the infiltration of CD3+ T-lymphocytes was not significantly affected by either carvedilol or metoprolol treatment.


Figure 4
View larger version (57K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 CD3-, CD4- and CD8-T-lymphocytes infiltration. A representative immunohistochemical staining of CVB3-infected heart sections (CD4 in 4.1, CD8 in 4.2, infected (a) and infected/carvedilol (b)) showed the inflammatory T-lymphocytes infiltration in loose interstitial space and cardiomyocyte hypertrophy. Original magnifications, x20.

 
3.7. Link between cytokine expression, MMP expression, myocardial cell infiltration and hemodynamic function
The significant correlations between mRNA abundance of IL-1β, TNF-{alpha} and hemodynamic parameters such as dP/dtmax (r2>0.5; p<0.001), and dP/dtmin (r2>0.5; p<0.001) emphasize the relevance of these cytokines in left ventricular dysfunction in this treatment trial. In addition, this significant interaction of IL-1β and TNF-{alpha} with myocardial remodeling and myocardial cell infiltration is demonstrated by a significant correlation between the mRNA abundance of these cytokines (IL-1β, TNF-{alpha}) and MMP-8 and MMP-9, as well as to CD4+ T-lymphocytes infiltration (Fig. 5 and Table 2).


Figure 5
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Correlation between IL-1β mRNA abundance and dP/dtmax (a), IL-1 β mRNA abundance and dP/dtmin (b), IL-1 β mRNA abundance and MMP-8 mRNA abundance (c).

 


View this table:
[in this window]
[in a new window]

  		Table 2 Correlation between inflammation, cellular infiltration, MMP-activity and hemodynamic function expressed by r2 and P<0.05 were considered significant

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
Impairment of left ventricular function in the coxsackievirus B3 infected Balb/c mice was significantly improved by treatment with the non-selective adrenoreceptor antagonist, carvedilol, for 10 days post infection. In addition, carvedilol treatment showed significant effects on altered myocardial cytokine and MMP/TIMP mRNA abundance: The increased myocardial IL-1β and TGF-β1 mRNA abundance in the infected mice was significantly attenuated in the carvedilol treatment group. Furthermore, carvedilol treatment restored the IL-15 mRNA abundance to baseline levels and induced the IL-10 mRNA abundance in the uninfected mice as well as in the infected mice. In addition, increased mRNA levels of MMP-8 in the infected mice were significantly down regulated in response to carvedilol administration. Moreover, a relevant down-regulation of CD4+ T-lymphocytes and an up-regulation of CD8+ T-lymphocytes was produced by carvedilol treatment. The significant correlations between IL-1β and MMP-8 mRNA abundance and CD4+ T-lymphocytes, as well as the correlation between IL-1β mRNA abundance and hemodynamic parameters emphasize the importance of this cytokine with respect to the MMP/TIMP ratio and hemodynamic function. Therefore, the overall beneficial effect of carvedilol on the left ventricular function observed in the acute phase of coxsackieviral murine myocarditis may be a result of a concerted action of carvedilol on hemodynamics, myocardial inflammation and alteration of the ECM. These effects were not produced by metoprolol treatment, which indicates that these carvedilol specific effects cannot be attributed to β1-selective blocking agents.

4.1. Myocardial inflammation and alteration of the ECM
In this study, we showed a highly induced infiltration of myocardial T-lymphocytes, with a predominance of CD4+ T-lymphocytes. In the context of viral myocarditis, a close association between the extent of the myocardial inflammation and the alteration of the ECM is possible, since cytokines modulate the expression of MMPs and TIMPs. It is thought that proinflammatory cytokines (IL-1β and TNF-{alpha}) play an important role in influencing ECM protein expression. IL-1β may activate fibroblasts [20], which are involved in the remodeling process after myocardial injury via production of extracellular matrix proteins [21]. Moreover, over-expression of IL-1β and TNF-{alpha} correlates with the increase in MMP and the reduction in TIMP expression. Thomas et al. [22] showed that the increase in myocardial MMP-3 and MMP-9 in human heart failure is associated with abnormal LV-remodeling. Furthermore, the inhibition of TNF-{alpha} contributes to a reduced level of myocardial MMP-9 expression [23]. These observations are in line with this study, which demonstrates an association between proinflammatory cytokine expression (IL-1β and TNF-{alpha}) and the expression of all MMP-groups, as well as the decreased expression of TIMP-4.

In contrast to the proinflammatory IL-1β, IL-10 reduces the severity of the disease by attenuating the immune response. IL-10 also has the ability to inhibit the production of proinflammatory cytokines, including IL-1 and TNF-{alpha} [24]. Furthermore, Santin et al. [25] showed that IL-10 has antiviral effects by acting as a differentiation factor for the CD8+ T-lymphocytes. IL-15 is a cytokine with anti-viral properties, which acts as a growth factor and stimulates IFN-{gamma} production by CD8+ T-lymphocytes [26, 27]. IL-10 reduces the IL-15-mediated expression of IFN-{gamma}, without affecting T-lymphocyte proliferation and viral clearance [28]. This differential expression of IL-10 and IL-15 is also seen in this study, with a significant up-regulation of IL-10 mRNA abundance accompanied by a significant down-regulation of IL-15 mRNA abundance in the infected animals compared to controls.

4.2. Actions of carvedilol on inflammation and alteration of the ECM
Several reports have suggested that carvedilol may have an effect on myocardial inflammation and remodeling. Recently, in an experimental coxsackieviral myocarditis model, Lim et al. [12] showed that local expression of interleukin-1 receptor antagonist by plasmid DNA reduces mortality and myocardial inflammation. Barth et al. [29] reported that the increase in left ventricular IL-6 and IL-1β in norepinephrine-induced cardiac hypertrophy is completely abolished by inhibition of {alpha}- and β-adrenergic receptors with carvedilol. In support of these findings, treatment with carvedilol in coxsackievirus B3-infected mice caused a significant improvement in left ventricular function, combined with significant changes in cytokine expression especially IL-1β suppression. These changes in the cytokine profile were linked to a relevant shift in the infiltrating T-lymphocytes combined with an increased CVB-3 RNA abundance in the carvedilol-treated animals 10 days post infection. The CVB-3 RNA abundance was performed using semiquantitative RT-PCR. The increased replication of CVB-3 in the heart was confirmed by RNA/RNA in situ hybridization (data not shown). Noticeably, these different immunomodulatory effects on cytokine expression, inflammatory cell infiltration and CVB-3 RNA abundance by carvedilol were not reproduced by β1 selective blockade with metoprolol. However, this increased CVB-3 RNA abundance was not linked to an impairment in left ventricular function. Therefore, the degree of myocardial inflammation seems to be more important than CVB-3 RNA abundance for the depression of left ventricular dysfunction in this murine model of acute viral myocarditis. Nonetheless, due to the dynamic course of viral myocarditis, this increased CVB-3 RNA abundance as well as the modulation of the CD8+ T-lymphocytes at 10 days post infection, provides no definite information about the virus load in the myocardium over the whole infection period. Therefore, further studies with sequential analysis of virus load would enable the evaluation of the immunomodulatory effects of carvedilol on the virus load in this model.

In addition, treatment with carvedilol contributes to the reduction in MMP mRNA abundance, especially MMP-8. This link between myocardial cytokine expression and the imbalance of the MMP/TIMP profile is emphasized by the significant correlation between the IL-1β, TNF-{alpha} and MMP-8 mRNA abundance as well as parameters of hemodynamic function and CD4+ T-lymphocytes infiltration. Therefore, these effects on the MMP system can partially explain the restored myocardial collagen network with reduced myocardial collagen turnover, which attenuates LV-dysfunction. These effects were not achieved by β1-selective blockade with metoprolol in our murine myocarditis model.

In addition to the significant suppression of the proinflammatory cytokine IL-1β by carvedilol, the antiinflammatory cytokine IL-10 was up-regulated in both the uninfected and infected mice, which might be due to a predominance of the TH2 immune response.

Grimm et al. [30] have shown the antifibrotic properties of carvedilol by reducing levels of collagen type I, type III and fibronectin in hearts with chronic pressure overload. In this murine model of acute myocarditis, carvedilol reduced only the collagen type I expression, which might be due to the early time point after infection. Therefore, long-term treatment with carvedilol in mice infected with coxsackievirus B3 may have further effects on the extracellular matrix architecture by attenuating the changes in the collagen gene expression. This may have a beneficial effect on disease progression and the evolution to dilated cardiomyopathy following the viral infection.


   5. Conclusions
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
In a murine coxsackievirus-induced acute myocarditis model, we found that carvedilol treatment reduced myocardial IL-1β and MMP-8 mRNA abundance. IL-15 mRNA abundance was brought to the baseline levels. IL-10 mRNA abundance levels were induced, combined with a relevant decrease in CD4+ and an increased infiltration of the CD8+ T-lymphocytes. In addition, the carvedilol-treated group showed a significant improvement in left ventricular function. These effects were not produced by β1-selective blockade with metoprolol.

Despite several reports that support the involvement of carvedilol in the modulation of myocardial gene expression, the molecular mechanisms that underlie the multiple actions of carvedilol are yet to be uncovered. The spectrum of activity of carvedilol, a third-generation non-selective β-blocker with {alpha}1-blocking properties, can be extended to include anti-oxidant, immunomodulatory, cardioreparatory and antifibrotic characteristics.


   Acknowledgement
 
This research was supported by the Deutsche Forschungsgemeinschaft (DFG Pa 369/2-1, Pa 369/2-3, Pa 369/3-1).


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
1 The first two authors contributed equally to this work. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

  1. Pauschinger M., Doerner A., Kuehl U., et al. Enteroviral RNA replication in the myocardium of patients with left ventricular dysfunction and clinically suspected myocarditis. Circulation (1999) 99:889–895.[Abstract/Free Full Text]
  2. Noutsias M., Pauschinger M., Poller W.C., Schultheiss H.P., Kuhl U. Current insights into the pathogenesis, diagnosis and therapy of inflammatory cardiomyopathy. Heart Fail. Monit. (2003) 3:127–135.[Medline]
  3. Liu P.P., Mason J.W. Advances in the understanding of viral myocarditis. Circulation (2001) 104:1076–1082.[Free Full Text]
  4. Kasaian M.T., Whitters M.J., Carter L.L., et al. IL-2 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity (2002) 16:559–569.[CrossRef][Web of Science][Medline]
  5. Keira N., Tatsumi T., Matoba S., et al. Lethal effect of cytokine-induced nitric oxide and peroxynitrite on cultured rat cardiac myocytes. J. Mol. Cell. Cardiol. (2002) 34:583–596.[CrossRef][Web of Science][Medline]
  6. Wollert K.C., Drexler H. Interleukin-1 beta induces cardiac myocyte growth but inhibits cardiac fibroblast proliferation in culture. J. Clin. Invest. (1995) 95:2555–2564.[Web of Science][Medline]
  7. Bouluyt M.C., O'Neil L., Mededith A.L., et al. Alteration in cardiac gene expression during the transition from stable hypertrophy to heart failure: marked upregulation of genes encoding extracellular components. Circ. Res. (1994) 75:25–32.
  8. Spinale F.G. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ. Res. (2002) 90:520–530.[Abstract/Free Full Text]
  9. Eichler W., Friedrichs U., Thies A., et al. Modulation of matrix metalloproteinase and TIMP-1 expression by cytokines in human RPE cells. Invest. Ophthalmol. Vis. Sci. (2002) 43:2767–2773.[Abstract/Free Full Text]
  10. Pauschinger M., Knopf D., Petschauer S., et al. Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation (1999) 99:2750–2756.[Abstract/Free Full Text]
  11. Huber S.A., Polgar J., Schultheiss P., et al. Augmentation of pathogenesis of coxsackievirus B3 infections in mice by exogenous administration of interleukin-1 and interleukin-2. J. Virol. (1994) 68:195–206.[Abstract/Free Full Text]
  12. Lim B.-K., Choe S.-C., Shin J.-O., et al. Local expression of inteleukin-1 receptor antagonist by plasmid DNA improves mortality and decreases myocardial inflammation in experimental coxsackieviral myocarditis. Circulation (2002) 105:1278–1281.[Abstract/Free Full Text]
  13. Frishman W.H. Carvedilol. N. Engl. J. Med. (1998) 339:1759–1765.[Free Full Text]
  14. Ohtsuka T., Hamada M., Saeki H., et al. Comparison of effects of carvedilol versus metoprolol on cytokine levels in patients with idiopathic dilated cardiomyopathy. Am. J. Cardiol. (2002) 89:996–999.[CrossRef][Web of Science][Medline]
  15. Sia Y.T., Parker T.G., Tsoporis J.N., et al. Long-term effects of carvedilol on left ventricular function, remodeling, and expression of cardiac cytokines after large myocardial infarction in the rat. J. Cardiovasc. Pharmacol. (2002) 39:73–87.[CrossRef][Web of Science][Medline]
  16. Nakano A., Matsumori A., Kawamoto S., et al. Cytokine gene therapy for myocarditis by in vivo electroporation. Hum. Gene Ther. (2001) 12:1289–1297.[CrossRef][Web of Science][Medline]
  17. Li J., Schwimmbeck P.L., Tschöpe C., et al. Collagen degradation in a murine myocarditis model: relevance of matrix metalloproteinase in association with inflammatory induction. Cardiovasc. Res. (2002) 56:235–247.[Abstract/Free Full Text]
  18. Bristow M.R., Larrabee P., Minobe W., et al. Receptor pharmacology of carvedilol in the human heart. J. Cardiovasc. Pharmacol. (1992) 19(Suppl. 1):S68–S80.[CrossRef][Web of Science][Medline]
  19. Noutsias M., Pauschinger M., Ostermann K., et al. Digital image analysis system for the quantification of infiltrates and cell adhesion molecules in inflammatory cardiomyopathy. Med. Sci. Monit. (2002) 8:MT59–MT71.[Medline]
  20. Mikami S., Kawashima S., Kanazawa K., et al. Low-dose N-nitro-L-arginine methyl ester treatment improves survival rate and decrease myocardial injury in a murine model of viral myocarditis induced by coxsackievirus B3. Circ. Res. (1997) 81:504–511.[Abstract/Free Full Text]
  21. Agocha A., Sigel A.V., Eghbali-Webb M. Characterization of adult human heart fibroblasts in culture: a comparative study of growth, proliferation and collagen production in human and rabbit cardiac fibroblasts and their response to transforming growth factor-beta1. Cell Tissue Res. (1997 (Apr)) 288(1):87–93.[CrossRef][Web of Science][Medline]
  22. Thomas C.V., Coker M.L., Zellner J.L., et al. Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation (1998) 97:1708–1715.[Abstract/Free Full Text]
  23. Bradham W.S., Moe G., Wendt K.A., et al. TNF-{alpha} and myocardial metalloproteinases in heart failure: relationship to LV remodeling. Am. J. Physiol. Heart Circ. Physiol. (2002) 282:H1288–H1295.[Abstract/Free Full Text]
  24. Lee T.S., Chau L.Y., et al. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat. Med. (2002) 8(3):240–246.[CrossRef][Web of Science][Medline]
  25. Santin A.D., Hermonat P.L., Ravaggi A., et al. Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirus-specific CD8(+) cytotoxic T lymphocytes. J. Virol. (2000) 74(10):4729–4737.[Abstract/Free Full Text]
  26. Stumpf C., Lehner C., Yilmaz A., Daniel W.G., Garlichs C.D. Decrease of serum levels of the anti-inflammatory cytokine interleukin-10 in patients with advanced chronic heart failure. Clin. Sci. (Lon) (2003) 105:45–50.[CrossRef]
  27. Weng N.P., Liu K., Catalfamo M., Li Y., Henkart P.A. IL-15 is a growth factor and an activator of CD8 memory T cells. Ann. N.Y. Acad. Sci. (2002) 975:46–56.[CrossRef][Web of Science][Medline]
  28. Körholz D., Banning U., Bönig H., et al. The role of interleukin-10 (IL-10) in IL-15-mediated T-cell responses. Blood (1997) 90(11):4513–4521.[Abstract/Free Full Text]
  29. Barth W., Deten A., Bauer M., et al. Differential remodeling of the left and right heart after norepinephrine treatment in rats: studies on cytokines and collagen. J. Mol. Cell. Cardiol. (2000) 32:273–284.[CrossRef][Web of Science][Medline]
  30. Grimm D., Huber M., Jabusch H.C., et al. Extracellular matrix proteins in cardiac fibroblasts derived from rat hearts with chronic pressure overload: effects of beta-receptor blockade. J. Mol. Cell. Cardiol. (2001) 33(3):487–501.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Circ. Res.Home page
P. Blyszczuk, G. Kania, T. Dieterle, R. R. Marty, A. Valaperti, C. Berthonneche, T. Pedrazzini, C. T. Berger, S. Dirnhofer, C. M. Matter, et al.
Myeloid Differentiation Factor-88/Interleukin-1 Signaling Controls Cardiac Fibrosis and Heart Failure Progression in Inflammatory Dilated Cardiomyopathy
Circ. Res., October 23, 2009; 105(9): 912 - 920.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
A. W.Y. Chung, H. H. C. Yang, M. W. Radomski, and C. van Breemen
Long-Term Doxycycline Is More Effective Than Atenolol to Prevent Thoracic Aortic Aneurysm in Marfan Syndrome Through the Inhibition of Matrix Metalloproteinase-2 and -9
Circ. Res., April 25, 2008; 102(8): e73 - e85.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
C. Cheung, D. Marchant, E. K.-Y. Walker, Z. Luo, J. Zhang, B. Yanagawa, M. Rahmani, J. Cox, C. Overall, R. M. Senior, et al.
Ablation of Matrix Metalloproteinase-9 Increases Severity of Viral Myocarditis in Mice
Circulation, March 25, 2008; 117(12): 1574 - 1582.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
A. Riad, S. Bien, M. Gratz, F. Escher, M. M. Heimesaat, S. Bereswill, T. Krieg, S. B. Felix, H. P. Schultheiss, H. K. Kroemer, et al.
Toll-like receptor-4 deficiency attenuates doxorubicin-induced cardiomyopathy in mice
Eur J Heart Fail, March 1, 2008; 10(3): 233 - 243.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
S. Heymans, M. Pauschinger, A. De Palma, A. Kallwellis-Opara, S. Rutschow, M. Swinnen, D. Vanhoutte, F. Gao, R. Torpai, A. H. Baker, et al.
Inhibition of Urokinase-Type Plasminogen Activator or Matrix Metalloproteinases Prevents Cardiac Injury and Dysfunction During Viral Myocarditis
Circulation, August 8, 2006; 114(6): 565 - 573.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
E. A. Jankowska, P. Ponikowski, M. F. Piepoli, W. Banasiak, S. D. Anker, and P. A. Poole-Wilson
Autonomic imbalance and immune activation in chronic heart failure - Pathophysiological links
Cardiovasc Res, June 1, 2006; 70(3): 434 - 445.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
S. Rutschow, J. Li, H.-P. Schultheiss, and M. Pauschinger
Myocardial proteases and matrix remodeling in inflammatory heart disease
Cardiovasc Res, February 15, 2006; 69(3): 646 - 656.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Pauschinger, M.
Right arrow Articles by Tschope, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pauschinger, M.
Right arrow Articles by Tschope, C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?