EBM Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
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 Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dreger, H.
Right arrow Articles by Stangl, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dreger, H.
Right arrow Articles by Stangl, V.
Experimental Biology and Medicine 233:427-433 (2008)
doi: 10.3181/0710-RM-292
© 2008 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Characteristics of Catechin- and Theaflavin-Mediated Cardioprotection

Henryk Dreger, Mario Lorenz, Alexandra Kehrer, Gert Baumann, Karl Stangl and Verena Stangl1

Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie (Campus Mitte), Charité–Universitätsmedizin Berlin, D-10117 Berlin, Germany

1 To whom requests for reprints should be addressed at Medizinische Klinik m. S. Kardiologie und Angiologie (CCM), Charité – Universitätsmedizin Berlin, Charitéplatz 1, D – 10117 Berlin, Germany. E-mail: verena.stangl{at}charite.de


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Catechins and theaflavins–the main polyphenolic substances of green and black tea, respectively–exert a plethora of beneficial effects on the cardiovascular system. In a model of H2O2-mediated oxidative stress, we investigated the effects of epigallocatechin-3-gallate (EGCG) and theaflavin-3,3'-digallate (TF3) on neonatal rat cardiomyocytes. Pretreatment with EGCG or TF3 1 hr prior to induction of oxidative stress by H2O2 effectively protected cardiac myocytes as determined by measuring release of lactate dehydrogenase after 24 hrs. Longer pre-incubation times resulted in significant loss of protection. To enable further mechanistic insight, we investigated expression of antioxidative enzymes and activation of prosurvival signaling cascades. Whereas mRNA levels of glutathione peroxidase 3, superoxide dismutase 1, and catalase were not influenced by both polyphenols, heme oxygenase (HO-1) was selectively upregulated by EGCG—but not by TF3. However, inhibition of HO-1 did not diminish polyphenol-mediated cardioprotection. While EGCG and TF3 activated Akt, extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase, inhibition of these kinases did not attenuate polyphenol-mediated protection. Loading of cardiomyocytes with dichlorofluorescein revealed that intracellular levels of reactive oxygen species were significantly reduced after treatment with EGCG or TF3 as early as 30 mins after induction of oxidative stress. In conclusion, activation of prosurvival signaling kinases and upregulation of antioxidative enzymes do not play a major role in tea polyphenol-mediated cardioprotection.

Key Words: oxidative stress • cardiac myocytes • epigallocatechin-3-gallate • theaflavin-3,3'-digallate • heme oxygenase 1


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Ranking after water, tea represents the second most frequently consumed beverage worldwide and is one of the major sources of dietary polyphenols. Vast epidemiological data indicate an inverse correlation between incidence rates of cardiovascular diseases and tea consumption (1–3). These findings have prompted numerous studies with evidence that tea polyphenols exert a plethora of antioxidant, anti-inflammatory, antiproliferative, and antithrombotic effects (4).

Oxidative stress plays a major role in the pathophysiology of various cardiovascular diseases such as atherosclerosis and ischemia-reperfusion injury. It is characterized by elevated levels of partially reduced metabolites, for example, hydrogen peroxide, superoxide anions, and hydroxyl radicals. These reactive oxygen species (ROS) severely damage proteins, DNA, and lipids. Accordingly, treatment with antioxidants (5, 6), chelators (7), and antioxidative enzymes (8–11) has been suggested to improve cardiac function, enhance myocyte survival, and reduce infarction size in models of ischemia-reperfusion injury of the heart.

Both catechins and theaflavins—the major polyphenolic ingredients of green and black tea, respectively—are excellent electron donors and efficient scavengers of free radicals such as superoxide anions, singlet oxygen, nitric oxide, and peroxynitrite (12, 13). The beneficial cardiovascular effects of tea consumption have therefore been primarily attributed to the potent ROS scavenging properties of tea polyphenols. In addition, there is some evidence that the induction of endogenous antioxidative enzymes by tea polyphenols further contributes to their antioxidative effect. Wu et al. observed a PI3K/Akt-dependent induction of heme oxygenase 1 (HO-1) in human endothelial cells after treatment with epigallocatechin-3-gallate (EGCG) that led to protection against oxidative stress (14).

The aim of our study was to investigate whether EGCG and theaflavin-3,3'-digallate (TF3) protect cardiac myocytes against oxidative stress and to elucidate whether additional effects of tea polyphenols—beyond their radical scavenging properties—contribute to cardioprotection.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Primary Cardiomyocyte Cell Culture. Model of Oxidative Stress.
Cardiomyocytes were prepared as described previously (15) and treated with 50 µM EGCG (Sigma-Aldrich, Munich, Germany), 20 µM TF3 (kindly provided by Mitsui Norin Food Research Laboratories, Japan), or solvent (water) for 1, 4, 8, or 24 hrs. For induction of oxidative stress, cells were washed with phosphate-buffered saline (PBS) and incubated with 100 µM H2O2 for 30 mins in serum-free medium. For further experiments, cells were kept in serum-free M199 for up to 24 hrs (Fig. 1AGo).


Figure 1
View larger version (29K):
[in this window]
[in a new window]

  		Figure 1. EGCG and TF3 protect cardiomyocytes against H2O2-mediated cell damage. (A) Cells were pretreated with 50 µM EGCG, 20 µM TF3, or solvent for 1, 4, 8, or 24 hrs, followed by incubation with 100 µM H2O2 for 30 mins. (B) LDH release as a marker for cell damage was quantified 24 hrs after removal of H2O2 (n = 3, *P < 0.05 versus solvent + H2O2).

 
Inhibition of RNA and Protein Synthesis, HO-1, and Signaling Cascades.
Cardiomyocytes were incubated with inhibitors of HO-1 (10 µM tin protoporphyrin IX [SnPPIX], Frontier Scientific, Logan, UT); RNA polymerase II (5 µg/ml {alpha}-amanitin, Sigma-Aldrich, Munich, Germany); protein synthesis (1 µg/ml cycloheximide [CHX], Sigma-Aldrich, Munich, Germany); phosphoinositide kinase-3 (PI3K) (100 nM wortmannin, Calbiochem, Darmstadt, Germany); mitogen-activated protein kinase-1 (MEK1) (50 µM PD98059, Calbiochem, Darmstadt, Germany); p38 mitogen-activated protein kinase (p38 MAPK) (50 µM SB203580; Calbiochem, Darmstadt, Germany); or solvent (0.1% dimethyl sulfoxide [DMSO]) 30 mins before addition of tea polyphenols to the medium. After 1 hr, cardiomyocytes were washed and treated with or without H2O2 for 30 mins. Following removal of H2O2, cells were kept in serum-free medium for 24 hrs. Fresh inhibitors were added after each wash step to ensure sufficient inhibition throughout the experiment.

Determination of Lactate Dehydrogenase Release.
To provide a marker for cell damage, we quantified the release of lactate dehydrogenase (LDH) using the CytoTox-ONE Homogenous Membrane Integrity Assay (Promega, Mannheim, Germany) 24 hrs after removal of H2O2.

RNA Preparation and Real-Time Reverse Tran-scriptase Polymerase Chain Reaction (RT-PCR) Analysis.
Cardiomyocytes were treated with 50 µM EGCG, 20 µM TF3, or solvent for 1 hr, followed by a wash step and incubation for another 4 hrs with fresh, serum-free medium. Total RNA was extracted as described elsewhere (16), and cDNA was amplified by RT-PCR using a 5700 Sequence Detection System (Applied Biosystems, Foster City, CA). PCR primers for HO-1, glutathione peroxidase 3 (GPx3), superoxide dismutase 1 (SOD1), catalase, and the housekeeping gene hypoxanthine phosphoribosyltransferase cDNAs were purchased from TIB MOLBIOL (Berlin, Germany). Relative expression of target genes was normalized to expression under control conditions by the comparative Ct-method (2–{Delta}{Delta}ct).

To inhibit mRNA synthesis, myocytes were treated with 5 µg/ml {alpha}-amanitin 30 mins before addition of tea polyphenols. Fresh inhibitor was added after each wash step to ensure sufficient inhibition of RNA polymerase II throughout the experiment.

Western Blot Analysis.
Total cell extracts were prepared in RIPA buffer (50 mM Tris, [pH 7.5] 150 mM NaCl, 1% NP40, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate [SDS]) containing protease complete, (Roche Applied Science, Mannheim, Germany) and phosphatase inhibitors (10 mM sodium fluoride, 1 mM sodium orthovanadate). Cellular debris was removed by centrifugation. Protein content was determined using the Bradford method (Pierce, Rockford, IL). Total protein was subjected to SDS-polyacrylamide gel electrophoresis (PAGE) and membranes were probed with the phospho-specific antibodies against Akt, extracellular signal regulated kinase 1/2 (ERK 1/2), and p38 MAPK (Cell Signaling, Beverly, MA). Western blots were stripped and reprobed against total {alpha}-actin (Sigma-Aldrich, Munich, Germany) as a loading control.

Measurement of Intracellular Reactive Oxygen Species Formation.
Cardiomyocytes were loaded for 30 mins at 37°C in the dark with 25 µM dichlorofluorescein diacetate (DCFDA, Invitrogen, Karlsruhe, Germany). DCFDA is cleaved by cellular esterases to nonfluorescent dichlorofluorescein, which is oxidized by intracellular ROS to the fluorescent product dichlorofluorescein. Stained cells were treated for 1 hr with 50 µM EGCG, 20 µM TF3, or solvent, followed by a wash step and incubation with 100 µM H2O2 in PBS buffer for 30 mins. Cardiomyocytes were then trypsinized, and fluorescence was quantified in a CyAn ADP flow cytometer (DakoCytomation, Glostrup, Denmark).

Statistics.
Data are expressed as mean ± SEM. We calculated significance by t-test or one-way ANOVA where appropriate (SPSS 11.0, Chicago, IL). An error probability of P < 0.05 was regarded as significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Tea Polyphenols Protect Cardiomyocytes Against Oxidative Stress.
Pretreatment of myocytes with EGCG (50 µM) and TF3 (20 µM) completely abolished H2O2-induced LDH release as a marker for cell damage when tea polyphenols were added 1 hr before H2O2. Longer incubation times from 4 to 24 hrs resulted in significant decrease and eventual complete loss of tea polyphenol-mediated cardioprotection (Fig. 1BGo).

Induction of Antioxidative Enzymes Is Not Requisite for Tea Polyphenol-Mediated Cardioprotection.
To elucidate whether upregulation of antioxidative enzymes contributes to the observed protective effects, we measured mRNA levels of SOD1, GPx3, and catalase in cardiomyocytes. mRNA levels of these antioxidative enzymes were not affected by EGCG or TF3 treatment (Fig. 2AGo, left panel). However, EGCG significantly induced the expression of HO-1 mRNA by 3.9-fold. This upregulation was prevented by pretreatment with the RNA polymerase II inhibitor {alpha}-amanitin, which suggests de novo synthesis of HO-1 mRNA. In contrast, TF3 failed to significantly increase HO-1 mRNA levels (Fig. 2AGo, right panel).


Figure 2
View larger version (28K):
[in this window]
[in a new window]

  		Figure 2. Tea polyphenols confer cardioprotection independently of induction of antioxidative enzymes. (A) mRNA expression of SOD1, GPx3, catalase, and HO-1, 5 hrs after treatment with 50 µM EGCG, 20 µM TF3, or solvent for 1 hr. Where indicated, RNA synthesis was inhibited by incubation with 5 µg/ml {alpha}-amanitin (n = 3, *P < 0.05 versus solvent control). (B) LDH release, 24 hrs after induction of oxidative stress by incubation with H2O2. Myocytes were pretreated with inhibitors of HO-1 (10 µM tin protoporphyrin IX, SnPPIX), mRNA synthesis (5 µg/ml {alpha}-amanitin), or protein synthesis (1 µg/ml cycloheximide, CHX). 30 mins after treatment with inhibitors, 50 µM EGCG or 20 µM TF3 were added for 1 hr, followed by incubation with 100 µM H2O2 for 30 mins (n = 3, *P < 0.05 versus solvent + H2O2). Since TF3 did not induce HO-1 expression, it was not included in experiments using SnPPIX as an HO-1 inhibitor.

 
Next, we addressed the question of whether induction of HO-1 or de novo synthesis of other cellular antioxidative enzymes contributes to tea polyphenol-mediated cardioprotection. We accordingly pretreated cardiomyocytes with the HO-1 inhibitor SnPPIX, the RNA polymerase II inhibitor {alpha}-amanitin, and the protein synthesis inhibitor cycloheximide, 30 mins before incubation of cells with EGCG or TF3. As depicted in Figure 2BGo, none of the above inhibitors significantly modulated polyphenol-mediated cardioprotection after challenging cells with H2O2 as assessed by quantification of LDH release (Fig. 2BGo).

Tea Polyphenol-Mediated Cardioprotection Does Not Depend on Activation of Protective Signaling Cascades.
To gain further insights into the mechanisms contributing to EGCG- and TF3-dependent reduction of cell damage after oxidative stress, we analyzed major signaling kinases involved in the regulation of apoptosis by phospho-specific immunoblotting. Treatment of cells with EGCG or TF3 resulted in pronounced phosphorylation, that is, activation of Akt, ERK 1/2, and p38 MAPK (Fig. 3AGo). To determine whether activation of these kinases is requisite for the observed tea polyphenol-mediated cardioprotection, we pretreated myocytes with inhibitors of PI3K (wortmannin), MEK1 (PD98059), and p38 MAPK (SB203580), 30 mins before incubation of cells with EGCG or TF3. As shown in Figure 3BGo, cardioprotection by EGCG and TF3 remained unaffected by inhibition of any of these kinases (Fig. 3BGo).


Figure 3
View larger version (25K):
[in this window]
[in a new window]

  		Figure 3. Tea polyphenols confer cardioprotection independently of activation of protective signaling cascades. (A) Western blots of phospho-Akt, phospho-ERK1/2, phospho-p38 MAPK, and {alpha}-actin, 1 hr after treatment with 50 µM EGCG or 20 µM TF3. (B) LDH release, 24 hrs after induction of oxidative stress by incubation with H2O2. Myocytes were pretreated with inhibitors of PI3K (100 nM wortmannin), MEK1 (50 µM PD98059), or p38 MAPK (50 µM SB203580). Thirty mins after treatment with inhibitors, 50 µM EGCG or 20 µM TF3 were added for 1 hr, followed by incubation with 100 µM H2O2 for 30 mins (n = 3, *P < 0.05 versus solvent + H2O2).

 
EGCG and TF3 Suppress ROS Formation.
Since the upregulation of antioxidative enzymes and the activation of prosurvival kinases are evidently not involved in EGCG-and TF3-mediated cardioprotection, we investigated the ability of both tea polyphenols to suppress ROS levels. After loading myocytes with a fluorescent marker for intracellular ROS, treatment with EGCG or TF3 significantly reduced ROS-mediated fluorescence as early as 30 mins after induction of oxidative stress (Fig. 4Go). These data suggest that the beneficial effects of tea polyphenols are due to their ability to directly scavenge free radicals.


Figure 4
View larger version (13K):
[in this window]
[in a new window]

  		Figure 4. Tea polyphenols suppress ROS formation. Myocytes were loaded with 25 µM DCFDA for 30 mins, and treated with 50 µM EGCG or 20 µM TF3 for 1 hr, followed by induction of oxidative stress with 100 µM H2O2. Cells were trypsinized 30 mins after addition of H2O2 (n = 3, *P < 0.05 versus solvent + H2O2).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Here we show that both EGCG and TF3—the main polyphenols in green and black tea, respectively—are capable of protecting cardiac myocytes against oxidative stress. Pretreatment with these polyphenols for 1 hr completely abolished H2O2-induced cellular damage, whereas longer pre-incubation times resulted in rapid decrease of polyphenol-mediated protection. In accordance with the half-life of the polyphenols in cell culture, the beneficial effects of EGCG and TF3 were completely lost after pre-incubation of 24 and 8 hrs, respectively (17, 18). Since upregulation of endogenous antioxidants would be expected to result in more delayed and sustained cardioprotection, our observations argue for direct protective properties of these polyphenols.

In concurrence with our findings, polyphenol-mediated cytoprotection has primarily been attributed to the ability of polyphenols to effectively scavenge free radicals (19). However, a number of studies in different cell types suggest additional effects of polyphenols. Townsend and coworkers demonstrated inhibition of apoptosis by EGCG-mediated activation of signal transducer and activator of transcription-1 (STAT-1) in cardiac myocytes during postischemic reperfusion (20). In an in vivo model of myocardial infarction, Aneja et al. observed ameliorated myocardial damage after treatment with EGCG that correlated with reduced degradation of nuclear factor {kappa}B inhibitor {alpha} (I{kappa}B{alpha}) and nuclear factor {kappa}B activity (21). In addition, Negishi et al. reported upregulation of catalase in aortas of spontaneously hypertensive rats after oral consumption of green tea polyphenols (22). Whereas the expression of SOD1, GPx3, and catalase remained unaffected by both polyphenols in cardiac myocytes, we observed selective upregulation of HO-1 by EGCG. In a recent study, induction of HO-1 in cardiac myocytes by resveratrol—a polyphenolic phytoalexin found in red grapes—was shown to reduce infarction size in an in vivo model of myocardial ischemia reperfusion injury (23). Upregulation of HO-1 by EGCG, therefore, may in fact contribute to its protective effects on cardiac myocytes. Indeed, Wu and coworkers recently demonstrated that induction of HO-1 by EGCG in endothelial cells correlated with protection against oxidative stress (14). In our study, however, direct inhibition of HO-1 as well as inhibition of RNA and protein synthesis did not diminish EGCG-mediated protection of cardiac myocytes which indicates that upregulation of HO-1 plays no major role in cardioprotection by EGCG.

To obtain further insights into the underlying mechanisms involved in antioxidative protection, we assessed the effects of both polyphenols on prosurvival pathways in cardiomyocytes. Both EGCG and TF3 activated Akt, ERK 1/2, and p38 MAPK that are known to exert anti-apoptotic effects (24–26). Surprisingly, inhibition of these pathways did not significantly influence the protective effects of tea polyphenols—which indicates that activation of these signaling cascades is not required for EGCG- and TF3-mediated cardioprotection.

While a recent publication suggests that EGCG itself exerts oxidant activities (27), we did not observe an increase of ROS levels after treatment with EGCG alone. On the contrary, further experiments revealed a suppression of ROS levels by polyphenol treatment as early as 30 mins after induction of oxidative stress.

The polyphenol concentrations used in our model are well within the range of doses employed by most previous in vitro studies (14, 20). However, due to the low bioavailability of catechins and theaflavins, tea consumption results in polyphenol plasma levels that are considerably lower (28). Therefore, further in vivo studies are needed to confirm our data.

Taken together, EGCG and TF3 render protection in cardiomyocytes against oxidative stress independently of upregulation of antioxidative enzymes or activation of prosurvival kinases.


   Acknowledgments
 
We thank Minoo Moobed and Wanda Michaelis for their excellent technical assistance.

Received for publication October 29, 2007. Accepted for publication December 3, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Geleijnse JM, Launer LJ, Van der Kuip DA, Hofman A, Witteman JC. Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study. Am J Clin Nutr 75:880–886, 2002.[Abstract/Free Full Text]
  2. Hertog MG, Feskens EJ, Kromhout D. Antioxidant flavonols and coronary heart disease risk. Lancet 349:699, 1997.[Medline]
  3. Kuriyama S, Shimazu T, Ohmori K, Kikuchi N, Nakaya N, Nishino Y, Tsubono Y, Tsuji I. Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. JAMA 296:1255–1265, 2006.[Abstract/Free Full Text]
  4. Stangl V, Dreger H, Stangl K, Lorenz M. Molecular targets of tea polyphenols in the cardiovascular system. Cardiovasc Res 73:348–358, 2007.[Abstract/Free Full Text]
  5. Horwitz LD, Fennessey PV, Shikes RH, Kong Y. Marked reduction in myocardial infarct size due to prolonged infusion of an antioxidant during reperfusion. Circulation 89:1792–1801, 1994.[Abstract/Free Full Text]
  6. Sethi R, Takeda N, Nagano M, Dhalla NS. Beneficial effects of vitamin E treatment in acute myocardial infarction. J Cardiovasc Pharmacol Ther 5:51–58, 2000.[Abstract/Free Full Text]
  7. Vanden Hoek TL, Shao Z, Li C, Zak R, Schumacker PT, Becker LB. Reperfusion injury on cardiac myocytes after simulated ischemia. Am J Physiol 270:H1334–H1341, 1996.[Medline]
  8. Chen Z, Siu B, Ho YS, Vincent R, Chua CC, Hamdy RC, Chua BH. Overexpression of MnSOD protects against myocardial ischemia/reperfusion injury in transgenic mice. J Mol Cell Cardiol 30:2281–2289, 1998.[CrossRef][Medline]
  9. Temsah RM, Netticadan T, Chapman D, Takeda S, Mochizuki S, Dhalla NS. Alterations in sarcoplasmic reticulum function and gene expression in ischemic-reperfused rat heart. Am J Physiol 277:H584–H594, 1999.[Medline]
  10. Woo YJ, Zhang JC, Vijayasarathy C, Zwacka RM, Englehardt JF, Gardner TJ, Sweeney HL. Recombinant adenovirus-mediated cardiac gene transfer of superoxide dismutase and catalase attenuates postischemic contractile dysfunction. Circulation 98:II255–II260, 1998.[Medline]
  11. Wang P, Chen H, Qin H, Sankarapandi S, Becher MW, Wong PC, Zweier JL. Overexpression of human copper, zinc-superoxide dismutase (SOD1) prevents postischemic injury. Proc Natl Acad Sci U S A 95:4556–4560, 1998.[Abstract/Free Full Text]
  12. Jovanovic SV, Simic MG. Antioxidants in nutrition. Ann N Y Acad Sci 899:326–334, 2000.[Medline]
  13. Paquay JB, Haenen GR, Stender G, Wiseman SA, Tijburg LB, Bast A. Protection against nitric oxide toxicity by tea. J Agric Food Chem 48: 5768–5772, 2000.[CrossRef][Medline]
  14. Wu CC, Hsu MC, Hsieh CW, Lin JB, Lai PH, Wung BS. Upregulation of heme oxygenase-1 by Epigallocatechin-3-gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways. Life Sci 78:2889–2897, 2006.[CrossRef][Medline]
  15. Stangl K, Günther C, Frank T, Lorenz M, Meiners S, Röpke T, Stelter L, Moobed M, Baumann G, Kloetzel PM, Stangl V. Inhibition of the ubiquitin-proteasome pathway induces differential heat-shock protein response in cardiomyocytes and renders early cardiac protection. Biochem Biophys Res Commun 291:542–549, 2002.[CrossRef][Medline]
  16. Meiners S, Hocher B, Weller A, Laule M, Stangl V, Guenther C, Godes M, Mrozikiewicz A, Baumann G, Stangl K. Downregulation of matrix metalloproteinases and collagens and suppression of cardiac fibrosis by inhibition of the proteasome. Hypertension 44:471–477, 2004.[Abstract/Free Full Text]
  17. Hong J, Lu H, Meng X, Ryu JH, Hara Y, Yang CS. Stability, cellular uptake, biotransformation, and efflux of tea polyphenol (-)-epigallocatechin-3-gallate in HT-29 human colon adenocarcinoma cells. Cancer Res 62:7241–7246, 2002.[Abstract/Free Full Text]
  18. Jhoo JW, Lo CY, Li S, Sang S, Ang CY, Heinze TM, Ho CT. Stability of black tea polyphenol, theaflavin, and identification of theanaphthoquinone as its major radical reaction product. J Agric Food Chem 53:6146–6150, 2005.[Medline]
  19. Urquiaga I, Leighton F. Plant polyphenol antioxidants and oxidative stress. Biol Res 33:55–64, 2000.[Medline]
  20. Townsend PA, Scarabelli TM, Pasini E, Gitti G, Menegazzi M, Suzuki H, Knight RA, Latchman DS, Stephanou A. Epigallocatechin-3-gallate inhibits STAT-1 activation and protects cardiac myocytes from ischemia/reperfusion-induced apoptosis. FASEB J 18:1621–1623, 2004.[Abstract/Free Full Text]
  21. Aneja R, Hake PW, Burroughs TJ, Denenberg AG, Wong HR, Zingarelli B. Epigallocatechin, a green tea polyphenol, attenuates myocardial ischemia reperfusion injury in rats. Mol Med 10:55–62, 2004.[CrossRef][Medline]
  22. Negishi H, Xu JW, Ikeda K, Njelekela M, Nara Y, Yamori Y. Black and green tea polyphenols attenuate blood pressure increases in stroke-prone spontaneously hypertensive rats. J Nutr 134:38–42, 2004.[Abstract/Free Full Text]
  23. Das S, Fraga CG, Das DK. Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFkappaB. Free Radic Res 40:1066–1075, 2006.[CrossRef][Medline]
  24. Baines CP, Molkentin JD. STRESS signaling pathways that modulate cardiac myocyte apoptosis. J Mol Cell Cardiol 38:47–62, 2005.[CrossRef][Medline]
  25. Hoover HE, Thuerauf DJ, Martindale JJ, Glembotski CC. alpha B-crystallin gene induction and phosphorylation by MKK6-activated p38. A potential role for alpha B-crystallin as a target of the p38 branch of the cardiac stress response. J Biol Chem 275:23825–23833, 2000.[Abstract/Free Full Text]
  26. Matsui T, Nagoshi T, Rosenzweig A. Akt and PI 3-kinase signaling in cardiomyocyte hypertrophy and survival. Cell Cycle 2:220–223, 2003.[Medline]
  27. Elbling L, Weiss RM, Teufelhofer O, Uhl M, Knasmueller S, Schulte-Hermann R, Berger W, Micksche M. Green tea extract and (-)-epigallocatechin-3-gallate, the major tea catechin, exert oxidant but lack antioxidant activities. FASEB J 19:807–809, 2005.[Abstract/Free Full Text]
  28. Lambert JD, Yang CS. Cancer chemopreventive activity and bioavailability of tea and tea polyphenols. Mutat Res 523–524:201–208, 2003.




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
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 Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dreger, H.
Right arrow Articles by Stangl, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dreger, H.
Right arrow Articles by Stangl, V.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS