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European Journal of Heart Failure 2007 9(2):152-159; doi:10.1016/j.ejheart.2006.05.007
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© 2007 European Society of Cardiology

Tea catechins improve left ventricular dysfunction, suppress myocardial inflammation and fibrosis, and alter cytokine expression in rat autoimmune myocarditis

Jun-ichi Suzuki*, Masahito Ogawa, Hideki Futamatsu, Hisanori Kosuge, Yuko M. Sagesaka and Mitsuaki Isobe

Department of Cardiovascular Medicine, Tokyo Medical and Dental University Tokyo 113-8519, Japan, and Central Research Institute, ITO EN, LTD., Shizuoka, Japan

* Corresponding author. Tel.: +81 03 5803 5951; fax: +81 03 5803 0133. E-mail address: jsuzuki.cvm{at}tmd.ac.jp


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
Background: Myocarditis is a clinically serious disease. Tea catechins have been shown to reduce inflammation; however the effects of catechins on the development of myocarditis have not been well studied.

Aims: To clarify the role of catechins, using an experimental autoimmune myocarditis (EAM) model.

Methods and results: Lewis rats were immunized with porcine cardiac myosin to establish EAM. Tea catechins were administered orally from day 0 to day 21 (Group A, n=12), from day 14 to day 21 (Group B, n=8), or saline (Group C, n=9) daily. Rats were killed on day 21. Echocardiograms indicated that Group A showed significantly improved cardiac function compared to Group C. Pathologically, non-treated EAM hearts showed severe myocardial cell infiltration and fibrosis; however Group A showed significantly less area. Immunohistochemistry revealed enhanced expression of NF-{kappa}B and ICAM-1 in non-treated EAM hearts, which was suppressed by catechin administration in Group A. mRNA levels of TNF-{alpha} were decreased and Th2 cytokines were markedly enhanced in Group A compared with the control group. Late catechin administration (Group B) showed limited effects on EAM.

Conclusion: The catechins suppressed ventricular remodelling in EAM; thus catechin treatment might be a promising option for the prevention of EAM myocarditis.

Key Words: Myocardial remodelling • Myocarditis • Inflammation • Echocardiogram • Cytokine • Nuclear factor

Received August 24, 2005; Revised January 13, 2006; Accepted May 11, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
Myocarditis is a serious disease in humans. Patients with myocarditis in its severest form may suffer from rapidly progressive heart failure, shock, or arrhythmia [1-7]. Although several immunomodulatory treatment strategies have shown beneficial effects in acute myocarditis [6-10], we are unable to treat all severe cases despite using multiple drug therapy and left ventricular assist devices. Thus, further evaluation of the immune mechanism of acute myocarditis is required in order to find alternative treatments.

Catechins are key components of green tea and have many biological functions, including anti-inflammatory, anti-oxidative and anti-carcinogenic effects [11-14]. These effects are induced by the suppression of inflammatory factors including nuclear factor-kappa B (NF-{kappa}B), a multipotential promoter of inducible nitric oxide synthase (iNOS) and adhesion molecules [15]. The major tea catechins are epigallocathechin-3 gallate (EGCG), epigallocathechin (EGC), and epicathechin-3 gallate (ECG). While the characteristics of green tea catechins have been well documented [16], their effects on acute myocarditis have not been well investigated.

Experimental autoimmune myocarditis (EAM) is a rat model which is characterized by severe myocardial damage and multinucleated giant cell infiltration. Although a typical experimental model of human acute myocarditis is viral myocarditis [17,18], this EAM model has been widely used as a disease model of human acute myocarditis [19-23]. Therefore, we used the EAM model to analyze the effect of catechins on the development of acute myocarditis.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
2.1. Animals and immunization
Male Lewis rats (7-weeks-old; body weight 200 to 250 g) were purchased from Sankyo Laboratories (Tokyo, Japan). They were fed a standard diet and water and were maintained in compliance with animal welfare guidelines of the Institute of Experimental Animals, Tokyo Medical and Dental University. Purified porcine cardiac myosin (Sigma Chemical Co., St. Louis, MO) was dissolved in 0.01 M phosphate-buffered saline (PBS) and emulsified with an equal volume of complete Freund's adjuvant supplemented with Mycobacterium tuberculosis H37RA (Difco, Sparks, MD) at a concentration of 10 mg/mL. On day 0, rats were injected in the footpads subcutaneously with 0.2 mL of emulsion, yielding an immunizing dose of 1.0 mg/body of cardiac myosin per rat [21-23].

2.2. Catechin administration
We used green tea catechins THEA-FLAN 90S (ITO EN, LTD. Tokyo, Japan) which includes EGCG: 45.2% ECG: 13.7% and EGC: 0.23% in this study. The immunized rats were randomly assigned to three groups as follows. Group A received catechins (20 mg/kg/day) from day 0 to day 21 (n=12), Group B received catechins (20 mg/kg/day) from day 14 to day 21 (n=8) and Group C received saline without catechins and acted as the controls (n=9). All treatments were administered orally. Native rat hearts were used as negative controls.

2.3. Echocardiogram
Transthoracic echocardiography was performed on the animals anesthetized by intra-peritoneal administration of pentobarbital sodium on day 14 and day 21. An echocardiography machine with a 7.5-MHz transducer (Nemio, Toshiba Co., Tokyo, Japan) was used for M-mode left ventricular echocardiographic recording. A 2D targeted M-mode echocardiogram was obtained along the short-axis view of the left ventricle at the papillary muscles. Left ventricular fractional shortening (LVFS) was calculated from M-mode echocardiograms over three consecutive cardiac cycles according to the American Society for Echocardiography leading edge method [24,25]. Pericardial effusion was also observed using the B-mode echocardiogram. To analyze cardiac function, two investigators measured the contraction independently, and the values were averaged.

2.4. Histopathology
Hearts were harvested immediately after the rats were killed and heart and body weight (g) were measured. Five transverse sections per heart were obtained for histological examination. Apex, midventricular, and basal level slices were stained with hematoxylin and eosin (HE) or Mallory staining. The area of the myocardium affected by cell infiltration was determined as infiltrated areas; fibrosis and necrotic changes were calculated as fibrotic areas. The areas were measured using a computerized analyzer (Scion Image beta 4.0.2). The area ratio (infiltration or fibrotic areas/entire area as a percentage) was calculated as described previously [21-23,26]. Values for three ventricular regions were averaged for each heart, and the mean percentage of affected area for each group was calculated. To analyze the histopathology, two independent investigators, who were blinded to the slide identification, measured the cell infiltrating area and fibrosis area using a computer analysis system, and the values were averaged.

2.5. Immunohistochemistry
Immunohistochemistry was used to examine CD4, CD8, CD11b, intercellular adhesion molecule (ICAM)-1, and NF-{kappa}B expression in the hearts. Briefly, frozen sections were fixed in 4% paraformaldehyde dissolved in PBS for 8 min at 4 °C. To stain CD4, CD8, CD11b (monoclonal antibodies from PharMingen, San Diego, CA), ICAM-1, or NF-{kappa}B (monoclonal antibodies from Santa Cruz Biotechnology, Inc., Santa Cruz, CA), sections were incubated with unlabelled primary antibodies (each at 1 to 10 µg/mL) for 8 h at room temperature (RT), washed in PBS, followed by biotinylated secondary antibodies (PharMingen) at 5 µg/mL for 45 min at 4 °C. After washing in PBS, the sections were incubated and visualized by incubating with an aminoethylcarbazole (AEC) complex (Nichirei Co. Tokyo, Japan). Sections were counterstained with hematoxylin solution (Sigma) [27].

2.6. Ribonuclease protection assay (RPA)
Trizole (Life Technologies, Bethesda, MD) was used to isolate mRNA according to the manufacturer's protocol. The probe was synthesized by the in vitro transcription method with a Multi-Probe Template Set (PharMingen), T7 polymerase, and [32P]UTP. 10 µg of total RNA was hybridized with the probe at 56 °C for 16 h. All samples were then treated with RNase before treatment with proteinase K. Samples were separated by electrophoresis on a 5% acrylamide denaturing gel. mRNA bands were detected with an image analyzer (BAS2000, Fujifilm, Tokyo, Japan). mRNA levels were quantified and normalized against levels of GAPDH. The normalized level of mRNA in each control group was expressed as 1.0 [27].

2.7. T cell proliferation assay
Spleen cells were isolated from rats with myocarditis on day 18. Cells (5x105/well) were cultured in 96-well culture plates with 50 µg/mL purified porcine heart myosin. The catechins were added to each well at various concentrations. Cultures were incubated at 37 °C under 5% CO2 for 3 days. Similarly, spleen cells isolated from rats in the control group were cultured with purified porcine heart myosin at various concentrations. T cell proliferation was assessed with the Cell Counting Kit-8 (Dojindo, Tokyo, Japan). Cell proliferation was expressed as optical density [27].

2.8. Enzyme-linked immunosorbent assay (ELISA)
Supernatant was collected from cultures used for T cell proliferation assays. Concentrations of interleukin (IL)-2 were determined with an ELISA kit (BioSource International, Camarillo, CA) according to the manufacturer's instructions [27].

2.9. Statistical analysis
Values are given as mean±SD. Groups were compared with Scheffe's ANOVA (Stat View, SAS Institute, Inc.). Differences were considered statistically significant at a value of P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
3.1. Effect of catechins on cardiac function
Non-treated EAM rats (Group C) showed reduced (32.0±1.7%) left ventricular fractional shortening (LVFS) compared to native rat hearts (53.0±1.2%, p<0.05 vs. Group C). However, catechin administration from day 0 to day 21 (Group A) significantly improved LVFS (51.3±1.9%, p<0.05 vs. Group C). EAM hearts in Group B showed impaired LVFS (36.0±1.0%), and there was no statistical difference between Groups B and C. Although pericardial effusion was observed in Groups B and C, the hearts in Group A and native rats showed almost no effusion (Fig. 1).


Figure 01
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  		Fig. 1 Representative M-mode and B-mode echocardiogram findings. Non-treated EAM rats (group C) showed reduced left ventricular fractional shortening (LVFS) and pericardial effusion on day 21 (panels A and C), catechin administration from day 0 to day 21 (group A) improved LVFS and suppressed pericardial effusion (panels B and D). LV: left ventricle, PE: pericardial effusion.

 
3.2. Effect of catechins on heart weight/body weight ratios
Non-treated EAM hearts (Group C) demonstrated an increased heart weight/body weight ratio (0.7±0.2%) compared to that of native rats (0.3±0.1%, p<0.05). Catechin administration in Group A significantly reduced the ratio (0.4±0.1%, p<0.05) compared to that of Group C. However, the ratio in Group B (0.6±0.3%) was comparable to that of Group C.

3.3. Effect of catechins on myocardial cell infiltration and fibrosis
Non-treated control EAM animals (Group C) showed severe myocardial cell infiltration (42.4±2.5%) and fibrotic lesions (44.6±2.8%) which were composed of extensive necrosis. However, catechin treatment from day 0 to day 21 (Group A) showed significantly less myocardial cell infiltration (29.0±2.6%, p<0.05 vs. Group C) and fibrosis (24.9±2.1%, p<0.05 vs. Group C) compared to Group C (Figs. 2 and 3). Late phase catechin administration from day 14 to day 21 (Group B) showed limited effects on cell infiltration (42.5±0.5%) and fibrosis (46.5±3.5%); there was no statistical difference between Groups B and C. Native rat hearts showed no cell infiltration and fibrosis.


Figure 02
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  		Fig. 2 Representative pathological results of Mallory staining in high (x200, A and C) and low (x2, B and D) power microscopic fields are presented. Non-treated control EAM animals (group C, n=9) showed severe myocarditis lesion that was composed of extensive fibrosis (A and B). However, catechin treatment from day 0 to day 21 (group A, n=12) showed significantly less fibrotic area (C and D).

 


Figure 03
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  		Fig. 3 Representative pathological results of HE staining in high (x200, A and C) and low (x2, B and D) power microscopic fields are presented. Non-treated control EAM animals (group C, n=9) showed giant cells, extensive necrosis, severe infiltration by mononuclear cells and polymorphonuclear neutrophils (A and B). However, the catechin treatment group (group A, n=12) showed significantly suppressed the infiltration (C and D).

 
3.4. Effect of catechins on CD4, CD8 and CD11b positive cell infiltration
Immunohistochemistry revealed enhanced expression of CD4, CD8, or CD11b on infiltrating cells in non-treated EAM hearts (Group C), while catechin administration in Group A significantly suppressed the expression (Fig. 4). ICAM-1 and NF-{kappa}B were enhanced on the myocardial infiltrating cells and arterial endothelial cells in Group C, although the expression of both ICAM-1 and NF-{kappa}B was suppressed in the catechin treated hearts in Group A (Fig. 5). Native rat hearts showed no enhanced expression of these factors.


Figure 04
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  		Fig. 4 Representative results of immunohistochemistry (x200) detecting for CD4 (A and B), CD8 (C and D) and CD11b (E and F) are shown. Enhanced infiltration densities of CD4, CD8, and CD11b were observed in non-treated EAM hearts (n=9, group C), while the catechin treatment from day 0 to day 21 (group A, n=12) suppressed the expression.

 


Figure 05
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  		Fig. 5 Representative results of immunohistochemistry (x200) detecting for ICAM-1 (A and B), and NF-{kappa}B (C and D) are shown. Enhanced expression of ICAM-1 and NF-{kappa}B was observed in no treated EAM hearts (n=9, group C), while the catechins (group A, n=12) suppressed the expression.

 
3.5. Cytokine mRNA expression
RPA was used to examine expression of cytokine mRNA in hearts. mRNA levels of TNF-{alpha}, which is a proinflammatory cytokine were markedly decreased in Group A (n=6) compared with Group C (n=6). However, mRNA levels of Th2 cytokines such as IL-4 and IL-10 in Group A were markedly enhanced compared with Group C (Fig. 6).


Figure 06
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  		Fig. 6 Representative results of ribonuclease protection assay. Levels of TNF-{alpha} mRNA were markedly decreased in the catechin-treated group (group A) compared with that of control (group C). However, catechin treatment (group A) enhanced levels of Th2 cytokines such as IL-4 and IL-10 (n=6 per group).

 
3.6. Suppression of cell proliferation
We performed cell proliferation assays to examine the effect of the catechins on antigen-induced T cell proliferation (n=6 per group). Antigen-induced T cell proliferation was suppressed by the catechins (Fig. 7).


Figure 07
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  		Fig. 7 Representative results of mixed lymphocyte reaction. Antigen-induced spleen cell proliferation was suppressed by the catechins (n=6 per group).

 
3.7. Th1-type cytokine changes
ELISA analysis of supernatant after incubation of spleen cells with cardiac myosin revealed that production of IL-2 was suppressed by the catechin treatment compared to the controls (n=6 per group) (Fig. 8).


Figure 08
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  		Fig. 8 Representative results of ELISA using supernatant after incubation of spleen cells with cardiac myosin. Production of IL-2 in the catechin treated group was suppressed compared to group C (n=6 per group).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 Acknowledgments
 References
 
Polyphenols, especially catechins, are the most significant components of tea [28]. Many biological functions of polyphenols have been studied [29], including anti-oxidative [30], anti-carcinogenic [31], anti-inflammatory [32], and anti-proliferative [33] effects. These effects are induced by several mechanisms such as the binding of NF-{kappa}B to the promoters of iNOS and adhesion molecules [34]. While these characteristics of catechins have been well documented, anti-inflammatory effects in cardiovascular diseases have not been well investigated. In this study, we investigated the effects of the catechins on left ventricular remodelling after acute myocarditis using rat EAM models.

Our results have demonstrated that catechin intake from day 0 to day 21 significantly suppressed the progression of myocardial cell infiltration and fibrosis with altered expression of NF-{kappa}B, adhesion molecules and cytokines. NF-{kappa}B is a key factor for development of acute myocarditis; we have previously shown that specific inhibition of NF-{kappa}B using a decoy in inflamed EAM hearts significantly suppressed the progression [22]. The NF-{kappa}B decoy suppressed many inflammatory factors including adhesion molecules, cytokines, and iNOS. Tea catechins have been shown to reduce iNOS mRNA expression in lipopolysaccharide- and interferon-activated mouse peritoneal cells by competitively inhibiting the binding of arginine and tetrahydrobiopterin [15]. It has also been reported that tea catechins block the induction of iNOS by down-regulating lipopolysaccharide-induced activity of the NF-{kappa}B [35]. Since NF-{kappa}B activation is also the cause of myocardial cell damage, the tea catechins play a significant role in the progression of disease.

We have shown that tea catechins suppressed myocardial cell infiltration and fibrosis with altered expression of Th1/Th2 cytokines. Changes in expression of Th1-type cytokines caused by the catechins in response to cardiac myosin were analyzed using RPA and ELISA, because EAM in Lewis rats is mediated by the Th1 response [23]. We found that production of TNF-{alpha} and IL-2 was reduced, whereas production of IL-4 and IL-10 was enhanced by catechin administration. This suggests that the altered Th1/Th2 balance is important in the regulation of EAM development. Catechin is known to be a suppressor not only of inflammatory cytokines but also of several growth factors which induce fibrosis. Oral administration of catechin significantly reduced consequent fibrosis in a pulmonary inflammation model [36]. Catechins inhibit the gene expression of the PDGF receptor by blocking the activation of transcription factors activator protein-1 and NF-{kappa}B. Because PDGF plays a critical role in myocardial remodelling and fibrosis [37], the catechins have significant beneficial effects in the treatment of chronic heart failure associated with myocardial fibrosis. These results provide molecular and cellular insights into the beneficial properties of green tea and indicate that EGCG is a potent anti-inflammatory compound with therapeutic potential.

As we and other investigators have reported [19-23], the non-treated EAM hearts showed cell infiltration and pericardial effusion on day 14, although the hearts on day 12 did not show any inflammation. This experimental time point (day 14 in EAM) is almost equal to the clinical time point when patients are referred to a clinic and receive medical treatment of acute myocarditis. Therefore, catechin treatment from day 14 to 21 (Group B) was a trial for the treatment of EAM. As we have shown, late-phase administration of catechins 14 to 21 days after EAM establishment did not have an effect on suppression of myocarditis. This is similar to previously reported data using the murine cardiac transplantation model; catechins suppressed chronic rejection but did not alter acute rejection [38]. Thus, administration of catechins may be useful for the prevention of recurrence and chronic remodelling after myocarditis.

Since typical human acute myocarditis is caused by viral infection [17,18], the effect of catechins should also be studied using experimental viral myocarditis models. It has been reported that immunosuppression, which would hypothetically have similar effects on the immune system as the catechins did in this model, has shown no beneficial effects in myocarditis patients with viral persistence [6]. In such patients, antiviral treatment seems to be a more promising approach [7,8]. However, there are some papers indicating that catechins have significant and direct antiviral effects [39,40]. Therefore, this in vivo administration may be effective not only for autoimmune myocarditis but also viral myocarditis.

This study has some limitations. Firstly, no blockade of catechins was undertaken as "proof of principle", this is because no specific inhibitor of catechins is currently available. Secondly, there were no different dosages of catechin supplementation to prove a dose-dependency of the observed effects. The dosage used in this study was physiological, we did not use a higher dosage as this may have caused adverse effects. Thus, further studies should be conducted to clarify the catechin effect in myocarditis and other inflammatory diseases.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
Acknowledgments
 References
 
Tea catechins suppress the development of EAM with altered expression of several inflammatory factors. Therefore, catechin treatment might be a promising option for the prevention of EAM myocarditis and other inflammatory cardiovascular diseases.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
References
 
This study was supported by grants from the Japan Cardiovascular Research Foundation, a Grant-in-aid from the Japanese Ministry of Education, Science and Culture, a Grant-in-aid from the Japanese Ministry of Welfare, the Mochida Memorial Foundation, and the Organization for Pharmaceutical Safety and Research. We thank Ms. Noriko Tamura and Ms. Yasuko Matsuda for their excellent assistance.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 

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Positive inotropic effects of epigallocatechin-3-gallate (EGCG) involve activation of Na+/H+ and Na+/Ca2+ exchangers
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