Skip Navigation

Cardiovascular Research 2006 69(1):272-279; doi:10.1016/j.cardiores.2005.07.009
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
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 Suzuki, J.-i.
Right arrow Articles by Isobe, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Suzuki, J.-i.
Right arrow Articles by Isobe, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2005, European Society of Cardiology

Tea catechins attenuate ventricular remodeling and graft arterial diseases in murine cardiac allografts

Jun-ichi Suzukia,*, Masahito Ogawaa, Yuko M. Sagesakab and Mitsuaki Isobea

aDepartment of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
bCentral Research Institute, Ito-en Co., 21 Mekami, Sagara, Haibara, Shizuoka 421-0516, Japan

* Corresponding author. Tel.: +81 3 5803 5951; fax: +81 3 5803 0133. Email address: jsuzuki.cvm{at}tmd.ac.jp

Received 30 November 2004; revised 7 July 2005; accepted 11 July 2005


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Objective: Tea catechins have many biological functions; these effects are induced by the suppression of several inflammatory factors. However, effects of catechins on cardiac allograft rejection have not been well investigated.

Methods and results: To test the hypothesis that catechins can attenuate ventricular remodeling and graft arterial diseases (GAD) in cardiac rejection, we orally administered catechins to murine cardiac recipients. We analyzed the mechanisms using immunohistochemistry, RNase protection, gel mobility shift, and cell proliferation assays. Although severe myocardial cell infiltration, fibrosis, and GAD with enhancement of inflammatory factors were observed in untreated class II mismatch allografts at day 60, catechins attenuated these changes with altered Th1/Th2 cytokine balance and suppressed NF-{kappa}B activation and cell proliferation.

Conclusion: Catechins are potent agents for the suppression of chronic rejection because they are critically involved in the suppression of proinflammatory signaling pathways.

KEYWORDS Cardiac transplantation; Rejection; Artery; Inflammation; Polyphenol; Mice


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Cardiac transplantation has been established in humans, however acute rejection and graft arterial diseases (GAD) are still problems [1,2]. Acute rejection is characterized by myocardial remodeling such as cell infiltration, necrosis and fibrosis; these problems are enhanced by several cytokines and adhesion molecules. GAD, that is considered as chronic rejection, is characterized by intimal thickening comprised of proliferative smooth muscle cells (SMCs) [3–5].

Catechins are key components of green tea with many biological functions, including anti-inflammatory, anti-oxidative and anti-carcinogenic effects [6–9]. These effects are induced by the suppression of several inflammatory factors including nuclear factor-kappa B (NF-{kappa}B), a multipotential promoter of inducible nitric oxide synthase (iNOS) and adhesion molecules [10]. The major tea catechins are epigallocathechin-3 gallate (EGCG), epigallocathechin (EGC), epicathechin-3 gallate (ECG). While these characteristics of tea catechins have been well documented [11], their effects on cardiac allograft rejection have not been well investigated.

NF-{kappa}B plays a pivotal role in the coordinated transcription of multiple inflammatory genes [12–14]. Recently, we have reported that decoy against the cis element of NF-{kappa}B prevents acute rejection and GAD by suppressing expression of multiple genes [15]. Since NF-{kappa}B decoy inhibits inflammatory gene expression, we hypothesized that tea catechins could suppress myocardial remodeling and GAD formation via NF-{kappa}B and related inflammatory factor regulation. In this study, we have demonstrated that tea catechins reduced both myocardial remodeling and GAD formation with supression of NF-{kappa}B activation, altered Th1/Th2 cytokine balances and suppressed cell proliferation.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1 Mice and cardiac transplantation
Male inbred mice (4–6 weeks, 20–25 g) were used in this study. A full allomismatch combination, C57BL/10Sn Slc (B/10, H2-b, Sankyo Laboratory Service Co., Tokyo, Japan) to C3H/HeN Jcl (C3H, H2-k, Clea Japan Inc., Tokyo, Japan) was used for analyzing acute rejection indicated by graft survival. C57BL/6 (B/6, H-2b) and B6.C-H-2bm12 KhEg (Bm12, H-2bm12) combination was used as the class II mismatch combination for analyzing chronic rejection indicated by pathological findings such as GAD and ventricular remodeling. Isografts (B/6 to B/6) were used for negative control. They were anesthetized by intraperitoneal injection of 3.6 % hydrochloride (0.2 ml/20 g, Wako Pure Chemical Industries, Ltd., Osaka, Japan) as reported previously [16–19]. Allografts were heterotopically transplanted in an intra-abdominal location using the microsurgical technique. Briefly, this technique involves anastomosing the end of the donor aorta to the side of the recipient abdominal aorta, after which the donor pulmonary artery is connected to the inferior vena cava of the recipient mice to return myocardial blood flow. Ischemic time averaged 60 min, and the overall success rate was greater than 90% [16–20]. This investigation conforms with the Guide for the Care and Use of Laboratory Animals in the Tokyo Medical and Dental University conform to NHI Guidelines.

2.2 Tea catechin administration
The transplanted mice were assigned randomly to two groups. The recipient mice were orally supplemented with tea catechins (20 mg/kg/day, THEA-FLAN 90S (Ito-en Co. Shizuoka, Japan) which includes EGCG: 45.2% ECG: 13.7% EGC: 0.23%) daily. This ratio is the natural dose ratio in the extracts from green tea. For control, transplanted mice were supplemented with normal water without the catechins.

2.3 Mice condition and graft function
We observed mice condition daily; we measured mice body weight (HF-3200, A&D Company Ltd., Tokyo, Japan) of each mouse and averaged. Graft function was assessed by daily palpation and graft failure was defined as the absence of detectable beating. Full allomismatch grafts were harvested on the day of the absence of detectable beating; class II cardiac allografts were harvested at day 60 after transplantation [16–18].

2.4 Histological examination and morphometry
We harvested the grafts and measured each maximal dimension and weight. Grafts were sectioned transversely at the maximal circumference of the ventricle. As previously described [16–18], serial sections (6 µm) from tissue embedded in OCT were stained with hematoxylin and eosin (HE), Mallory and Elastica van Gieson (EvG) to highlight the internal elastic lamina (IEL). The grafts were photographed and processed using an image analysis system to calculate the area of cell infiltration and fibrosis. The areas of myocardial cell infiltration (consisting of inflammatory cells and myocardial necrosis) using HE staining and fibrosis using Mallory staining were determined with a computer-assisted analyzer (Scion Image beta 4.0.2). The area ratio was calculated as (affected area X100)/whole area (%) as described [18,19,21]. Values for three ventricular regions were averaged for each heart, and the mean percentage of affected area for each group was calculated.

The graft arteries were also photographed, videodigitized and processed using an image analysis system (NIH Image). The area encompassed by the lumen and IEL was traced carefully, and the area of luminal stenosis in each cross-section was calculated according to the formula: luminal occlusion=(IEL area–luminal area) x 100/IEL area (%) as described. All data were analyzed in a blind fashion by two independent investigators and averaged [3,5,15,18–21].

2.5 Immunohistochemistry
Serial sections (6 µm) were cut and dipped in cold acetone for 10 min. The sections were rehydrated in PBS and incubated with 5% normal goat serum to block non-specific reactions. Sections were incubated with primary antibodies against murine intercellular adhesion molecule (ICAM)-1 (YN1/1.7), vascular cell adhesion molecule (VCAM)-1 (MK/2) (provided by Prof. Ko Okumura, Juntendo University), CD4 (#550278, PharMingen, BD Biosciences, San Jose, CA), CD8 (#550281, PharMingen), CD11b (#1561-01, Southern Biotechnology Associates Inc., Birmingham, AL), monocytes/macrophages (MOMA-2, #T-2007, BMA Biomedicals AG, Rheinstrasse, Switzerland), TGF-beta (#SC-146, Santa Cruz Biotechnology Inc., Santa Cruz, CA), and NF-{kappa}B (p65, #SC372, Santa Cruz) for 12 h at 4 °C [18–20]. Antibody-biotin conjugate was detected with Vectastain ABC Kit (Histofine Kit, Nichirei Co., Tokyo, Japan) used according to the manufacturer's instructions. Enzyme activity was detected with diaminobenzidine (0.5 mg/ml) with 0.05% NiCl in 50 mM Tris buffer, pH 7.5. Intensity of expression was scored as follows: 0, no visible staining; 1, few cells with faint staining; 2, few cells with moderate staining; 3, some cells with moderate staining; 4, diffuse cells with moderate staining; or 5, diffuse and intense staining [20]. Scores of two independent reviewers were averaged.

2.6 RNase protection assay (RPA)
The harvested allografts were homogenized in Trizol reagent (Life Technologies, Grand Island, NY) and frozen at –80 °C. Cytokine mRNA expression was measured by RPA using mCK1 template (Riboquant kit, PharMingen, San Diego, CA). Levels of mRNA expression were quantified and normalized to GAPDH mRNA using densitometry [18].

2.7 Mixed lymphocyte reaction (MLR)
Single-cell splenocyte suspensions were prepared by dissociating tissue with frosted glass slides. A total of 5 x 105 naive responder cells were cultured with an equal number of mitomycin-C treated stimulator cells in 96 well plates in C/10 media. The catechin was added to each well at concentrations of 10–8 M, 10–7 M, and 10–6 M which were considered as physiological levels. Cell proliferation was assessed with the Cell Counting Kit-8 (Dojindo, Tokyo, Japan) at 37 °C under 5% CO2 on day 3. Cell proliferation was expressed as the optical density [21].

2.8 Gel mobility shift assay
To prove the effect of catechins on NF-{kappa}B, we performed a gel mobility shift assay using the EMSA kit (AY1030K, Panomics Inc., Redwood City, CA). Briefly, nuclear extract from mice allografts was prepared from murine cardiac allografts treated with or without catechins. NF-{kappa}B primer (5'-AGTTGAGGGACTTTCCCAGGC-3') was biotin-labeled and incubated for 30 min and then loaded onto a 4% polyacrylamide gel. The gels were subjected to electrophoresis and electroblotting. We used nylon membranes (Biodyne B #60201, Pall Gelman Laboratory, Ann Arbor, MI) and SuperSignal West Dura Extended Duration Substrate (Pierce Biotechnology, Inc., Rockford, IL). We have performed this gel-shift assay using 4 samples for each group.

2.9 Statistical analysis
All data are expressed as mean ± SEM. Scores were compared among the groups using a Scheffe's ANOVA. Differences with values of P<0.05 were considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1 Graft survival and mice condition
Because we would like to confirm the effects of the catechin both on acute and chronic rejection, we have used a full-allomismatch and a class II allomismatch combinations. A full-allomismatch combination, C3H to B/10, did not prolong the graft survival statistically (Table 1), as we previously reported using another full-allomismatch combination C57BL/6 (H-2b) to BALB/c (H-2d) [22].


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

  		Table 1 Graft survival in the total allomismatch combination

 
The class II mismatch allograft recipients showed same body weight gain; there was no statistical difference among the groups (Table 2). All class II mismatch allografts beat on day 60; this means class II mismatch allografts survived more than 60 days without immunosuppressants in this combination.


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

  		Table 2 Body and graft weights and graft dimension in class II mismatch combinations on day 60

 
3.2 Macroscopical findings and weights of the grafts
Heart dimension and weight of the class II mismatch grafts on day 60 were measured. Although severely enlarged graft dimension and weight gain were observed in nontreated allografts, catechins markedly attenuated the heart dimension and weight gain, the score was statistically less than controls (Fig. 1, Table 2).


Figure 1
View larger version (73K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Representative microscopical findings of allografts of the class II mismatch group at day 60. Upper panels show myocardium stained with HE, and lower panels are Mallory staining. Nontreated allografts showed massive myocardial cell infiltration (A) and fibrois (B). Oral administration of tea catechin suppressed not only myocardial cell infiltration (C) but also fibrosis (D). (scale bars=1 mm).

 
3.3 Histological findings of the myocardium
Isografts and allografts of the class II mismatch group kept beating throughout the observation period. In the class II mismatch group, severe myocardial cell infiltration and fibrosis was observed in nontreated allografts at day 60. However, tea catechins markedly attenuated myocardial cell infiltration and fibrosis, the score was statistically less than controls (Fig. 1, Table 3). Native hearts and isografts showed very faint myocardial cell infiltration and fibrosis. Immunohistochemically, enhancement of CD4, CD8, CD11b, monocytes/macrophages, ICAM-1, and NF-{kappa}B expression was observed in nontreated allograft myocardium at day 60, mainly observed in interstitium with mononuclear cell infiltration. However, catechin transfection markedly attenuated expression of all these factors. Native hearts and isografts showed no myocardial ischemic changes and enhancement of these factors (Fig. 2, Table 3).


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

  		Table 3 Histological findings of the myocardium in class II mismatch allografts

 

Figure 2
View larger version (128K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Representative immunohistochemical findings of allografts of the class II mismatch group at day 60. Left panels show allografts from nontreated mice; right panels are from those treated with the catechins. CD8 (A), macrophages (C), ICAM-1 (E) and NF-{kappa}B (G) were strongly and diffusely expressed in the myocardial interstitium of allografts from untreated recipients, while expression of CD8 (B), macrophages (D), ICAM-1 (F) and NF-{kappa}B (H) was weak in allografts treated with tea catechins. (scale bars=5µm).

 
3.4 Histological findings of the graft arteries
Heavy neointimal thickening was observed in the coronary arteries of untreated allografts at day 60. However, arterial intimal thickening was attenuated in the catechin treated group. Immunohistochemically, CD4-, CD8-, CD11b-positive cells and macrophages were accumulated in the thickened intima of nontreated allografts, while these positive cell numbers were suppressed in the catechin treated allograft arteries. VCAM-1 and NF-{kappa}B (p65) were expressed strongly and diffusely in the thickened intima of arteries of nontreated allografts, while catechin treatment suppressed the expression. However, TGF-β was faintly expressed in the thickened intima of arteries of nontreated allografts as comparable in catechin-treated graft arteries (Fig. 3, Table 4).


Figure 3
View larger version (110K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Representative findings of allograft arteries of the class II mismatch group at day 60. Left panels show arteries from nontreated mice; right panels are from those treated with the catechins. Panels A and B show arteries with elastica van Gieson staining, and other panels (C–H) are immunohistochemical findings of the arteries. Severe intimal thickening (A) with enhanced expression of macrophages (C) and VCAM-1 (E) was observed in the nontreated arteries, while suppressed GAD development (B) and expression of macrophages (D) and VCAM-1 (F) was observed in the arteries with catechins. However, TGF-β was faintly expressed in the thickened intima of arteries of nontreated allografts (G) as comparable in catechin-treated graft arteries (H). (scale bars=5µm).

 

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

  		Table 4 Histological findings of the graft arteries in class II mismatch allografts

 
3.5 Altered cytokine mRNA expression by the catechins
RPA was used to examine expression of cytokine mRNA in hearts. Because previous papers indicated that IFN-{gamma} is a critical Th1 cytokine and IL-10 is a key Th2 cytokine in transplantation, we have chosen them to analyse this mechanism [23,24]. Levels of Th2 cytokine IL-10 was significantly elevated in the catechin treated group compared with that of non-treated group. However, Th1 cytokine IFN-{gamma} mRNA in the catechin treated groups was comparable. In addition, IL-6 was also comparable although IL-6 has been known to play a role in mediating inflammation (n=4 each, Fig. 4).


Figure 4
View larger version (33K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Representative RPA results using RNA from allografts are shown in panel A. Quantitative results of IFN-{gamma} (B), IL-10 (C), and IL-6 (D) mRNA are presented. IFN-{gamma} and IL-6 mRNA levels in the catechin treated groups were comparable with those of the control group. However, IL-10 was significantly elevated in the catechin treated group compared with that of non-treated group.

 
3.6 Suppression of cell proliferation by the catechins
We performed cell proliferation assays to examine the effect of the catechins on antigen-induced T cell proliferation. The cell proliferation was suppressed by the catechins (63% in 10–8 M, 68% in 10–7 M, 63% in 10–6 M reduction) in comparison to that in the control group (Fig. 5).


Figure 5
View larger version (25K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Representative results of cell proliferation assays are shown. Proliferation of cells treated with the catechins was reduced compared to cells in the control group.

 
3.7 Gel mobility shift assay
Gel mobility shift assay analysis documented that increased NF-{kappa}B binding activity was observed in nontreated allografts. This enhanced NF-{kappa}B binding was reduced by catechin administration (Fig. 6).


Figure 6
View larger version (47K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 6 Gel mobility shift assay analysis documented that increased NF-{kappa}B binding activity was observed in nontreated allografts (n=4). This enhanced NF-{kappa}B binding was reduced by catechin administration (n=4).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
Polyphenols, especially catechins, are the most potent component of green tea affecting cell function [25]. Many biological functions of polyphenols have been studied [26], including anti-oxidative [27], anti-carcinogenic [28,29], anti-inflammatory [30], and anti-proliferative [31] effects. These effects were induced by several mechanisms such as the binding of NF-{kappa}B to the promoters of iNOS and adhesion molecules [32]. While these characteristics of cathechins have been well documented, anti-inflammatory effects in cardiovascular diseases modulated by cathechins have not been well investigated.

Firstly, we have investigated the effects of catechins for preventing acute rejection using the full allomismatch combination; the non-treated allograft beats stopped within 15 days after transplantation. We tried to confirm the immunosuppressive effects of catechins using this model, however they do not have enough immunosuppressive effects because catechins could not prolong the graft survival statistically. The class II mismatch combination represents chronic rejection; these are clinically serious problems such as GAD and ventricular remodeling. We have demonstrated that the effects of catechins for preventing chronic rejection without systemic adverse effects. Because the recipient body weights were not different among the groups, we estimated the general conditions of the catechin treated-mice are as good as the control mice. Our results have demonstrated that the catechin intake significantly suppresses the expression of inflammatory factors including adhesion molecules and NF-{kappa}B. Especially, NF-{kappa}B is a key factor for the development of ventricular remodeling and GAD; we have revealed that specific inhibition of NF-{kappa}B using a decoy in rejected cardiac allografts significantly suppressed the progression. In the study, the NF-{kappa}B decoy suppresses many inflammatory factors including adhesion molecules, cytokines, and MHCs [15]. Although catechins are not specific inhibitors of NF-{kappa}B, they have similar effects such as suppression of adhesion molecules and other inflammatory factors. Because the amount of catechins usually present in a cup of green tea is 100–400 mg, an effective dosage of tea catechins could be achieved by drinking a few cups of tea per day [33].

We have reported a novel therapeutic strategy to attenuate myocardial cell infiltration and fibrosis in heart allografts, utilizing oral administration of catechins to suppress critical inflammatory genes and altered Th1/Th2 cytokine balances. The inhibitory effects of catechins on myocardial cell infiltration and fibrosis are supported by a few points of evidence. Firstly, catechins inhibit the expression of targeted multiple factors, including adhesion molecules [14], which are crucial for antigen presentation in transplanted organs. Secondly, catechins markedly alter Th1/Th2 cytokine balances which regulate the inflammatory network that includes rejection; an increased Th1/Th2 ratio indicates an increased contribution of Th1 related inflammation [7]. It is noteworthy that catechins have elevated the level of IL-10 which is a key member of Th2 cytokines, although IFN-{gamma} levels are comparable. Because the IL-10 decreases the Th1/Th2 balance and immune tolerance in cardiac transplantation, an increase of IL-10 means a suppression of Th1 related inflammation [2,34]. Therefore, a catechin-mediated increase in IL-10 expression indicates that these natural extracts suppress Th1 related inflammation via altered Th1/Th2 balances. IL-10 is an anti-inflammatory factor in these experiments and catechins are the suppressor of rejection via Th2 cytokine enhancement. This catechin strategy may provide a therapeutic modality in the treatment of ventricular remodeling after allograft rejection. We have also shown that the catechins suppress cell proliferation in MLR. This indicates the catechins suppress alloreaction between donor and recipient antigen presentation. Although these MLR results may not be related directly to cardiac rejection, this in vitro study has been widely used to analyze the alloreaction [18,24].

It is noteworthy that catechins not only attenuate ventricular remodeling but also suppress GAD formation in cardiac allografts. In general, myocardial fibrosis and remodeling are the consequence of acute rejection; the GAD is recognized as one of results of chronic rejection [2,3,15]. However, an immunosuppression such as FK506 suppresses myocardial cell infiltration while the drug does not suppress the GAD. Thus, several therapeutic trials have been undertaken to attenuate GAD but without widespread use [35,36]. In this study, we have demonstrated that the catechins inhibit intimal hyperplasia effectively. The prevention of neointimal formation was associated with suppressed expression of adhesion molecules; it can be deduced that NF-{kappa}B must play an important role in the SMC proliferation. NF-{kappa}B is widely known to be a key enhancer of inflammation, this stimulates SMC proliferation in GAD. Therefore, suppression of NF-{kappa}B activation reduces SMC proliferation. As we have previously reported, suppression of NF-{kappa}B using decoy oligonucleotide transfection decreased GAD formation [15]. Recent results have indicated that statins [37] and rapamycine [2] have the potential for suppressing GAD. Because the statins and the rapamycine also have anti-inflammatory effects via suppression of NF-{kappa}B activation, catechins have a potential for suppression of GAD in the same way. Although statins and rapamycine are effective for prevention of GAD, they may have systemic adverse effects. However, tea catechins may have effects without side effects, because they are natural extracts and millions of people have drunk them for more than several decades. In fact, several clinical trials have proved the safety and effects on cancer and other diseases [33,38,39].

In this report, we have demonstrated that oral administration of tea catechins attenuate both myocardial remodeling and GAD formation by inhibition of multiple inflammatory genes without systemic adverse effects. Further studies should be conducted in other models to explore the clinical utility of catechins for prevention of ventricular remodeling and arterial diseases.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 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 would like to thank Ms Noriko Tamura for excellent technical assistance.


   Notes
 
Time for primary review 21 days


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

  1. Taylor D.O., Edwards L.B., Boucek M.M., Trulock E.P., Keck B.M., Hertz M.I. The registry of the International Society for Heart and Lung Transplantation: twenty-first official adult heart transplant report-2004. J Heart Lung Transplant (2004) 23:796–803.[CrossRef][Web of Science][Medline]
  2. Pinney S.P., Mancini D. Cardiac allograft vasculopathy: advances in understanding its pathophysiology, prevention, and treatment. Curr Opin Cardiol (2004) 19:170–176.[CrossRef][Web of Science][Medline]
  3. Suzuki J., Isobe M., Aikawa M., Kawauchi M., Shiojima I., Kobayashi N., et al. Nonmuscle and smooth muscle myosin heavy chain expression in rejected cardiac allograft. A study in rat and monkey models. Circulation (1996) 96:1118–1124.[Web of Science]
  4. Hosenpud J.D. Immune mechanism of cardiac allograft vasculopathy: an update. Transplant Immunol (1993) 1237–1249.
  5. Suzuki J., Isobe M., Morishita R., Aoki M., Horie S., Okubo Y., et al. Prevention of graft coronary arteriosclerosis by antisense cdk2 kinase oligonucleotide. Nat Med (1997) 3:900–903.[CrossRef][Web of Science][Medline]
  6. Ishikawa T., Suzukawa M., Ito T., Yoshida H., Ayaori M., Nishiwaki M., et al. Effect of tea flavonoid supplementation on the susceptibility of low-density lipoprotein to oxidative modification. Am J Clin Nutr (1997) 66:261–266.[Abstract/Free Full Text]
  7. Junkun J., Selman S.H., Swiercz R., Skrzypczak-Jankun E. Why drinking tea could prevent cancer. Nature (1997) 387:561.[CrossRef][Medline]
  8. Beecher G.R., Warden B.A., Merken H. Analysis of tea polyphenols. Proc Soc Exp Biol Med (1999) 220:267–270.[CrossRef][Medline]
  9. Yang C.S., Landau J.M., Huang M.T., Newmark H.L. Inhibition of carcinogenesis by dietary polyphenolic compounds. Annu Rev Nutr (2001) 21:381–406.[CrossRef][Web of Science][Medline]
  10. Lin Y.L., Lin J.K. (–)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-kappaB. Mol Pharmacol (1997) 52:465–472.[Abstract/Free Full Text]
  11. Benelli R., Vene R., Bisacchi D., Garbisa S., Albini A. Anti-invasive effects of green tea polyphenol epigallocatechin-3-gallate (EGCG), a natural inhibitor of metallo and serine proteases. Biol Chem (2002) 383:101–105.[CrossRef][Web of Science][Medline]
  12. May M.J., Ghosh S. Signal transduction through NF-kappa B. Immunol Today (1998) 19:80–88.[CrossRef][Web of Science][Medline]
  13. Sha W.C. Regulation of immune responses by NF-kappa B/Rel transcription factor. J Exp Med (1998) 187:143–146.[Free Full Text]
  14. Barnes P.J., Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med (1997) 336:1066–1071.[Free Full Text]
  15. Suzuki J., Morishita R., Amano J., Kaneda Y., Isobe M. Decoy against nuclear factor-kappa B attenuates myocardial cell infiltration and arterial neointimal formation in murine cardiac allografts. Gene Ther (2000) 7:1847–1852.[CrossRef][Web of Science][Medline]
  16. Isobe M., Yagita H., Okumura K., Ihara A. Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1. Science (1992) 255:1125–1127.[Abstract/Free Full Text]
  17. Furukawa Y., Matsumori A., Hirozane T., Sasayama S. Angiotensin II receptor antagonist TCV-116 reduces graft coronary artery disease and preserves graft status in a murine model. A comparative study with captopril. Circulation (1996) 93:333–339.[Abstract/Free Full Text]
  18. Suzuki J., Cole S.E., Batirel S., Kosuge H., Shimizu K., Isobe M., et al. Tumor necrosis factor receptor-1 and -2 double deficiency reduces graft arterial disease in murine cardiac allografts. Am J Transplant (2003) 3:968–976.[CrossRef][Web of Science][Medline]
  19. Isobe M., Suzuki J., Yagita H., Okumura K., Yamazaki S., Nagai R., et al. Immunosuppression to cardiac allografts and soluble antigens by anti-vascular cellular adhesion molecule-1 and anti-very late antigen-4 monoclonal antibodies. J Immunol (1994) 153:5810–5818.[Abstract]
  20. Suzuki J., Isobe M., Yamazaki S., Horie S., Okubo Y., Sekiguchi M. Inhibition of accelerated coronary atherosclerosis with short-term blockade of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 in a heterotopic murine model of heart transplantation. J Heart Lung Transplant (1997) 16:1141–1148.[Web of Science][Medline]
  21. Futamatsu H., Suzuki J., Kosuge H., Yokoseki O., Kamada M., Ito H., et al. Attenuation of experimental autoimmune myocarditis by blocking activated T cells through inducible costimulatory molecule pathway. Cardiovasc Res (2003) 59:95–104.[Abstract/Free Full Text]
  22. Suzuki J., Ogawa M., Sagesaka Y.M., Isobe M. Catechins attenuate myocardial cell infiltration and fibrosis but do not prolong graft survival in murine cardiac allografts. Transplant Proc (2005) 37:119–120.[CrossRef][Web of Science][Medline]
  23. Nagano H., Mitchell R.N., Taylor M.K., Hasegawa S., Tilney N.L., Libby P. Interferon-gamma deficiency prevents coronary arteriosclerosis but not myocardial rejection in transplanted mouse hearts. J Clin Invest (1997) 100:550–557.[Web of Science][Medline]
  24. Furukawa Y., Becker G., Stinn J.L., Shimizu K., Libby P., Mitchell R.N. Interleukin-10 augments allograft arterial disease: paradoxical effects of IL-10 in vivo. Am J Pathol (1999) 155:1929–1939.[Abstract/Free Full Text]
  25. Scalbert A., Williamson G. Dietary intake and bioavailability of polyphenols. J Nutr (2000) 130(8S Suppl):2073S–2085S.[Abstract/Free Full Text]
  26. Weisburger J.H. Lifestyle, health and disease prevention: the underlying mechanisms. Eur J Cancer Prev (2002) 11(Suppl_2):S1–S7.[CrossRef][Medline]
  27. Aviram M., Dornfeld L., Kaplan M., Coleman R., Gaitini D., Nitecki S., et al. Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: studies in atherosclerotic mice and in humans. Drugs Exp Clin Res (2002) 28:49–62.[Web of Science][Medline]
  28. Lambert J.D., Yang C.S. Cancer chemopreventive activity and bioavailability of tea and tea polyphenols. Mutat Res (2003) 523–524:201–208.
  29. Kudo M., Naito Z., Yokoyama M., Asano G. Effects of quercetin and sunphenon on responses of cancer cells to heat shock damage. Exp Mol Pathol (1999) 66:66–75.[CrossRef][Web of Science][Medline]
  30. Takabayashi F., Harada N. Effects of green tea catechins (Polyphenon 100) on cerulein-induced acute pancreatitis in rats. Pancreas (1997) 14:276–279.[Web of Science][Medline]
  31. Locher R., Emmanuele L., Suter P.M., Vetter W., Barton M. Green tea polyphenols inhibit human vascular smooth muscle cell proliferation stimulated by native low-density lipoprotein. Eur J Pharmacol (2002) 434:1–7.[CrossRef][Web of Science][Medline]
  32. Lin J.K., Liang Y.C., Lin-Shiau S.Y. Cancer chemoprevention by tea polyphenols through mitotic signal transduction blockade. Biochem Pharmacol (1999) 58:911–915.[CrossRef][Web of Science][Medline]
  33. Chow H.H., Cai Y., Hakim I.A., Crowell J.A., Shahi F., Brooks C.A., et al. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res (2003) 9:3312–3319.[Abstract/Free Full Text]
  34. Suzuki J., Isobe M., Izawa A., Takahashi W., Yamazaki S., Okubo Y., et al. Differential Th1 and Th2 cell regulation of murine cardiac allograft acceptance by blocking cell adhesion of ICAM-1/LFA-1 and VCAM-1/VLA-4. Transplant Immunol (1999) 7:65–72.[CrossRef][Web of Science][Medline]
  35. Uretsky B.F., Murali S., Reddy P.S., Rabin B., Lee A., Griffith B.P., et al. Development of coronary artery disease in cardiac transplanted patients receiving immunosuppressive therapy with cyclosporine and predonisolone. Circulation (1987) 76:827–834.[Abstract/Free Full Text]
  36. Pollak R., Fabrega A.J. Diltazem in the prevention of coronary artery disease in heart-transplant recipients. N Engl J Med (1993) 28:1851–1852.
  37. See V.Y. Jr., DeNofrio D., Goldberg L., Chang G., Sasseen B., Kolansky D.M., et al. Effect of atorvastatin on postcardiac transplant increase in low-density lipoprotein cholesterol reduces development of intimal hyperplasia and progression of endothelial dysfunction. Am J Cardiol (2003) 92:11–15.[CrossRef][Web of Science][Medline]
  38. Moyers S.B., Kumar N.B. Green tea polyphenols and cancer chemoprevention: multiple mechanisms and endpoints for phase II trials. Nutr Rev (2004) 62:204–211.[CrossRef][Web of Science][Medline]
  39. Mukhtar H., Ahmad N. Tea polyphenols: prevention of cancer and optimizing health. Am J Clin Nutr (2003) 71:1698S–1702S.

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
 Cardiovasc ResHome page
K. Hishikari, J.-i. Suzuki, M. Ogawa, K. Isobe, T. Takahashi, M. Onishi, K. Takayama, and M. Isobe
Pharmacological activation of the prostaglandin E2 receptor EP4 improves cardiac function after myocardial ischaemia/reperfusion injury
Cardiovasc Res, January 1, 2009; 81(1): 123 - 132.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. Ogawa, J.-i. Suzuki, K. Hishikari, K. Takayama, H. Tanaka, and M. Isobe
Clarithromycin Attenuates Acute and Chronic Rejection Via Matrix Metalloproteinase Suppression in Murine Cardiac Transplantation
J. Am. Coll. Cardiol., May 20, 2008; 51(20): 1977 - 1985.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
J.-i. Suzuki, M. Ogawa, H. Futamatsu, H. Kosuge, Y. M. Sagesaka, and M. Isobe
Tea catechins improve left ventricular dysfunction, suppress myocardial inflammation and fibrosis, and alter cytokine expression in rat autoimmune myocarditis
Eur J Heart Fail, February 1, 2007; 9(2): 152 - 159.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
V. Stangl, H. Dreger, K. Stangl, and M. Lorenz
Molecular targets of tea polyphenols in the cardiovascular system
Cardiovasc Res, January 15, 2007; 73(2): 348 - 358.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
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 Suzuki, J.-i.
Right arrow Articles by Isobe, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Suzuki, J.-i.
Right arrow Articles by Isobe, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?