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(Circulation. 1998;98:794-799.)
© 1998 American Heart Association, Inc.

Basic Science Reports

Inhibitory Effects of Antioxidants on Neonatal Rat Cardiac Myocyte Hypertrophy Induced by Tumor Necrosis Factor- and Angiotensin II

Kazufumi Nakamura, MD; Kazuo Fushimi, PhD; Hirosuke Kouchi, MD; Koichiro Mihara, PhD; Masahiro Miyazaki, PhD; Tohru Ohe, MD; ; Masayoshi Namba, MD

From the Department of Cardiovascular Medicine (K.N., H.K., T.O.), Department of Anatomy (K.N.), and Department of Cell Biology, Institute of Molecular and Cellular Biology (K.F., K.M., M.M., M.N.), Okayama University Medical School, Japan.

Correspondence to Kazufumi Nakamura, MD, Department of Cardiovascular Medicine, Okayama University Medical School, 2–5-1 Shikata, Okayama 700-8558, Japan. E-mail cardio{at}cc.okayama-u.ac.jp

	Abstract

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Background—Tumor necrosis factor- (TNF-) and angiotensin II (Ang II) modulate heart failure in part by provoking the hypertrophic response. Signal transduction pathways of those factors are implicated in reactive oxygen intermediates (ROIs). Therefore, we hypothesized that TNF- and Ang II might cause myocyte hypertrophy via the generation of ROIs.

Methods and Results—To test the hypothesis, we tested whether TNF- and Ang II could induce the generation of ROIs and whether antioxidants such as butylated hydroxyanisole (BHA), vitamin E, and catalase might inhibit the hypertrophy in cultured neonatal rat cardiac myocytes. ROIs were measured by the ROI-specific probe 2',7'-dichlorofluorescin diacetate in cultured cardiac myocytes. We demonstrated that TNF- and Ang II induced the generation of ROIs in a dose-dependent manner. TNF- (10 ng/mL) and Ang II (100 nmol/L) enlarged cardiac myocytes and increased [³H]leucine uptake, and BHA (10 µmol/L) significantly inhibited both effects. Other antioxidants, such as vitamin E (1 µg/mL) and catalase (100 U/mL), also inhibited the enlargement of cardiac myocytes induced by TNF-.

Conclusions—These results indicate that TNF- and Ang II cause hypertrophy in part via the generation of ROIs in cardiac myocytes.

Key Words: myocytes • cells • hypertrophy • growth substances • antioxidants

	Introduction

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Cardiac myocyte hypertrophy is one of the most important features of many cardiac diseases. After excessive work or myocardial injury, adaptive cardiac myocyte hypertrophy occurs. Although cardiac hypertrophy is, at least initially, a favorable and adaptive mechanism that serves to maintain function, it is associated with poor prognosis because of an increased risk of arrhythmia and the development of congestive heart failure.^{1 2 3 4 5} Therefore, the elucidation of the mechanism of cardiac hypertrophy is important.

Recent studies show that circulating levels of tumor necrosis factor- (TNF-) and angiotensin II (Ang II) are elevated in patients with chronic heart failure, such as ischemic heart disease and dilated cardiomyopathy.^{6 7 8 9} Cardiac myocyte hypertrophy is a principal feature of such cardiac diseases,^{10 11} and TNF- and Ang II are regarded as important factors that can induce hypertrophy. Indeed, the direct effect of those factors on cardiac hypertrophy can be demonstrated in cultured cardiac myocytes.^{12 13 14 15}

Both TNF- and Ang II are implicated in reactive oxygen intermediates (ROIs). TNF- exerts cytotoxic activity on some types of tumor cells, in part via the generation of ROIs,^{16 17 18} and Ang II causes hypertension in vivo¹⁹ and c-Jun N-terminal kinase activation in cardiac myocytes,²⁰ in part via the generation of ROIs. ROIs are involved in many biological processes. For instance, they play an important role in the defense against microorganisms, or they can cause cell injury directly. Furthermore, ROIs take part in regulating of the expression of various genes and cell growth.^{21 22 23 24 25 26} In fact, ROIs specifically stimulate DNA synthesis and the expression of proto-oncogenes such as c-myc and c-fos in vascular smooth muscle cells.²¹ ROIs also mediate some Ang II–induced c-Jun–c-Fos heterodimer DNA binding activity and hypertrophic responses in myogenic cells.²⁴ Thus, we hypothesized that TNF- and Ang II might cause cardiac myocyte hypertrophy via the generation of ROIs. To test this hypothesis, we attempted to determine whether TNF- and Ang II exposure could generate ROIs and whether antioxidants such as BHA, vitamin E, and catalase could inhibit TNF-– and Ang II–induced hypertrophy in cultured neonatal rat cardiac myocytes.

	Methods

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Materials
Recombinant human TNF- was obtained from Genzyme Co; BHA from Wako Pure Chemical Industries Ltd; vitamin E (d--tocopherol), catalase, and angiotensin II from Sigma Chemical Co; 2',7'-dichlorofluorescin diacetate (DCFH-DA) from Molecular Probes Inc; and [³H]leucine from Moravek Biochemicals Inc.

Cell Culture
Primary cultures of cardiac myocytes were prepared from the ventricles of neonatal Wistar rats essentially by the method of Simpson.²⁷ Cardiocytes were maintained at 37°C in humidified air with 5% CO₂. After dissociation of the heart tissue with trypsin, cells were preplated for 1 hour into 100-mm culture dishes in DMEM (Nissui Pharmaceutical Co) with 10% FCS (Intergen Co) to reduce the number of nonmyocyte cells. Cells that were not attached to the preplated dishes were plated into 6-well culture plates (Falcon) at a density of 1x10³ cells/mm². Nonmyocytes in the cultures were limited to 10% of the total cell number by inclusion of bromodeoxyuridine (BrdU) (0.1 mmol/L) in the medium for the first 2 days. The culture medium was replaced after 24 hours with serum-free medium consisting of DMEM, transferrin (5 µg/mL), insulin (1 µg/mL), and BrdU (0.1 mmol/L). On culture day 4, the myocytes were treated with TNF-, Ang II, or their diluent, which consisted of PBS containing 0.1% BSA without TNF- or Ang II.

Cardiac Myocyte Surface Area
The myocyte surface area was measured by the method of Simpson.²⁷ Cell images, which were viewed with a video camera (Nikon) fixed to a microscope (Nikon), were projected onto a monitor and traced. Image analysis software (NIH Image 1.56) directed the computation of the myocyte area. The area was then doubled to account for the surface portion in contact with the dish. All cells from randomly selected fields in 2 or 3 wells were examined for each condition. We measured 100 cells in each condition. The myocyte area was determined after 3-day treatment with TNF-, Ang II, and antioxidants, in comparison with control cells treated with their diluent (PBS containing 0.1% BSA without TNF- or Ang II).

Analysis of Dichlorofluorescein Fluorescence
A fluorescent probe, 2',7'-dichlorofluorescin diacetate (DCFH-DA), was used for the assessment of intracellular ROI formation in cultured rat cardiac myocytes. The principle of this assay is that DCFH-DA diffuses through the cell membrane and is hydrolyzed by intracellular esterases to nonfluorescent dichlorofluorescin (DCFH). In the presence of ROIs, DCFH is rapidly oxidized to highly fluorescent dichlorofluorescein.²⁸ This assay is a reliable method for the measurement of intracellular ROIs such as hydrogen peroxide (H₂O₂), hydroxyl radical (·OH), and hydroperoxides (ROOH).^{28 29 30} DCFH-DA was dissolved in absolute ethanol at a concentration of 5 mmol/L. On culture day 4, cultured rat cardiac myocytes were washed with PBS containing Ca²⁺ and Mg²⁺ (PBS⁺), and then either TNF- (1 to 100 ng/mL), Ang II (1 to 1000 nmol/L), or diluent (control) was administered simultaneously with DCFH-DA (1 µmol/L) in 1 mL PBS⁺. After incubation at 37°C for 1 hour, cells were collected from culture plates with a cell scraper. The fluorescence intensity per culture-plate well was monitored on a Hitachi spectrofluorometer 650-10S with excitation wavelength at 485 nm (bandwidth, 5 nm) and emission wavelength at 530 nm (bandwidth, 10 nm). The fluorescence intensity for treated cells was determined in comparison with control cells (diluent only: PBS containing 0.1% BSA without TNF- or Ang II).

For fluorescence microscopy, cardiac myocytes were grown on collagen-coated glass coverslips in 6-well culture plates. On culture day 4, TNF- (10 ng/mL), Ang II (100 nmol/L), or their diluent (control) was administered simultaneously with DCFH-DA (5 µmol/L) in culture medium. After incubation at 37°C for 1 hour, cardiac myocytes were washed with PBS. Fluorescence images were acquired with a fluorescence microscope (Axiophot FL, Carl Zeiss Inc).

Incorporation of [³H]Leucine
To examine the effect of TNF- on protein synthesis, the incorporation of [³H]leucine was measured essentially by the method of Thaik et al.³¹ Cultured myocytes were treated with TNF- (10 ng/mL), Ang II (100 nmol/L), BHA (10 µmol/L), or diluent (control) and coincubated with [³H]leucine (1 µCi/mL) from culture day 4 to 7. The cells were washed with PBS and then treated with 5% trichloroacetic acid at 4°C for 1 hour to precipitate the protein. The precipitates were then dissolved in NaOH (0.1N). Aliquots were counted with a scintillation counter. [³H]leucine uptake for treated cells was compared with control cultures (diluent only: PBS containing 0.1% BSA without TNF- or Ang II).

Protein Content
Cultured myocytes were treated with TNF- (10 ng/mL), BHA (10 µmol/L), or diluent (control) from culture day 4 to 7. The cells were washed with PBS and then treated with 5% trichloroacetic acid as described above. The precipitates were dissolved in NaOH (0.1N). The protein content was measured by the Bio-Rad DC protein assay.

Statistical Analysis
All results are expressed as mean±SEM. Statistical analysis was performed by 1-way ANOVA, with comparison of different treatment groups by Fisher's protected least significant difference test. Values of P<0.05 were considered to be significant.

	Results

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Dose-Dependent Increase in Cardiac Myocyte Area by TNF- Exposure
Recent data showing that TNF- increased the incorporation of amino acids into cultured cardiac myocytes indicate that cardiac myocyte hypertrophy is induced by TNF-.^{12 13} Because cardiac hypertrophy is also characterized by the enlargement of myocytes,^{12 27} we examined the influence of TNF- exposure on both the incorporation of amino acid and myocyte surface area. The cultured neonatal rat cardiac myocytes exposed to TNF- (1 to 100 ng/mL) for 3 days increased their surface area in a dose-dependent manner (Figure 1A). The increase by treatment with 10 to 100 ng/mL TNF- was significant compared with controls (P<0.0001 at 10 ng/mL TNF-, n=100 cells).

View larger version (34K): [in this window] [in a new window]   Figure 1. A, Dose-dependent increase in cardiac myocyte area by TNF- exposure. Cultured cardiac myocytes were exposed for 3 days to TNF- (1 to 100 ng/mL) or diluent without TNF- (control). All cells from randomly selected fields in 2 or 3 wells were measured for each condition. Each data point is mean myocyte surface area±SEM (n=100 cells). *P<0.0001 vs control cultures treated with diluent. B and C, Dose-dependent increase in fluorescence due to TNF- and Ang II exposure. On culture day 4, cultured cardiac myocytes were treated with TNF- (1 to 100 ng/mL), Ang II (1 to 1000 nmol/L), or diluent without TNF- and Ang II (control) and simultaneously with DCFH-DA (1 µmol/L). After 1 hour of incubation, cells were collected and fluorescence intensity per culture well was measured. Each point is mean±SEM (n=5 experiments). In each experiment, a treated-to-control ratio was calculated from fluorescence intensity of 5 experiments. P<0.005, #P<0.01, ##P<0.0005 vs control cultures treated with diluent only.

Dose-Dependent Increase in Fluorescence by TNF- and Ang II Exposure
The cells incubated with TNF- and Ang II for 1 hour showed an increase of dichlorofluorescein fluorescence intensity per culture well in a dose-dependent manner (Figure 1B and 1C). In fact, TNF- (100 ng/mL)–treated groups and Ang II (100 and 1000 nmol/L)–treated groups showed a significant increase of fluorescence intensity compared with control groups (P<0.005, control versus 100 ng/mL TNF-; P<0.05, control versus 100 nmol/L Ang II; P<0005, control versus 1000 nmol/L Ang II; n=5 experiments).

For cardiac myocytes on glass coverslips, the increase in fluorescence induced by TNF- (10 ng/mL) or Ang II (100 nmol/L) exposure was also observed under a fluorescence microscope (Figure 2). These data indicate that both TNF- and Ang II generate ROIs in cardiac myocytes.

View larger version (122K): [in this window] [in a new window]   Figure 2. The increase of fluorescence due to TNF- and Ang II exposure. Representative living cardiac myocytes observed by fluorescence microscopy (A to C, G to I) and phase contrast microscopy (D to F, J to L). On culture day 4, cultured cardiac myocytes on glass coverslips were treated with diluent (control) (A, D, G, and J), TNF- (10 ng/mL) (B, E, H, and K), or Ang II (100 nmol/L) (C, F, I, and L) and with 2DCFH-DA (5 µmol/L). Treatment time was 1 hour. Top 2 lanes (A to F) at low magnification; lower 2 lanes (G to L) at high magnification. Bar=100 µm.

Inhibitory Effects of Antioxidants on TNF-– and Ang II–Induced Myocyte Enlargement
To examine whether myocyte hypertrophy induced by TNF- and Ang II was mediated by ROIs, antioxidants were added to myocyte cultures. TNF- (10 ng/mL) and Ang II (100 nmol/L) caused enlargement of the cardiac myocytes, but BHA (10 µmol/L) significantly inhibited this effect (P<0.0005, TNF- versus TNF- plus BHA, n=100 cells, Figures 3 and 4; P<0.0001, Ang II versus Ang II plus BHA, n=50 cells, Figure 3). To examine whether the antihypertrophic effect was specific to BHA, we used other antioxidants, such as vitamin E (1 µg/mL) and catalase (100 U/mL). Vitamin E and catalase significantly inhibited cardiac myocyte enlargement induced by TNF- (P<0.0001, TNF- versus TNF- plus vitamin E, n=100 cells; P<0.0001, TNF- versus TNF- plus catalase, n=100 cells; Figure 3). BHA, vitamin E, or catalase alone had no effect on myocyte surface area (P=NS, control versus BHA, vitamin E, or catalase, n=100 cells, Figure 3). These findings show that ROIs may mediate TNF-– and Ang II–induced myocyte hypertrophy.

View larger version (62K): [in this window] [in a new window]   Figure 3. Inhibitory effects of antioxidants on myocyte enlargement induced by TNF- and Ang II. On culture day 4, cardiac myocytes were treated with TNF-, Ang II, antioxidants (BHA, vitamin E, or catalase), or diluent without TNF- or Ang II (control). Myocyte surface area was determined after 3-day treatment with those factors. TNF- (10 ng/mL) or Ang II (100 nmol/L) was administered simultaneously with BHA (10 µmol/L), vitamin E (1 µg/mL), or catalase (100 U/mL). In each experiment, a treated-to-control ratio was calculated. Myocyte surface area was 1386±32 µm2/cell for control myocytes treated with diluent. Each point is mean±SEM (n=50 to 100 cells). C indicates control; Cat., catalase; VE, vitamin E; and A II, Ang II. *P<0.0001 vs control cultures treated with diluent, P<0.0005 and P<0.0001 vs TNF-, #P<0.0001 vs Ang II.

View larger version (144K): [in this window] [in a new window]   Figure 4. Inhibitory effects of BHA on TNF-–induced myocyte enlargement. Representative living cardiac myocytes treated as follows: top left, diluent (control); top right, BHA (10 µmol/L); bottom left, TNF- (10 ng/mL); and bottom right, TNF- (10 ng/mL) plus BHA (10 µmol/L). Treatment time was 3 days. Bar=100 µm.

Inhibitory Effects of BHA on TNF-– and Ang II–Induced [³H]Leucine Incorporation
There is a possibility that cell area could be altered by changes in cell shape or flattening; thus, we measured the incorporation of an amino acid and the protein content in cardiac myocytes to investigate the hypertrophic effect. TNF- (10 ng/mL) and Ang II (100 nmol/L) increased [³H]leucine incorporation (P<0.005, control versus TNF-, n=4 dishes; P<0.0001, control versus Ang II, n=8 dishes), but the increase was inhibited by BHA (10 µmol/L) (P<0.05, TNF- versus TNF- plus BHA, n=4 dishes; P<0.005, Ang II versus Ang II plus BHA, n=8 dishes; Figure 5A). BHA alone had no effect on [³H]leucine uptake (P=NS versus control, n=4 dishes, Figure 5A).

View larger version (48K): [in this window] [in a new window]   Figure 5. A, Inhibitory effects of BHA on [3H]leucine incorporation induced by TNF- and Ang II. Cultured myocytes were treated with TNF- (10 ng/mL), Ang II (100 nmol/L), BHA (10 µmol/L), or diluent without TNF- and Ang II (control) and were coincubated with [3H]leucine (1 µCi/mL) on culture day 4. After 3-day treatment, incorporated [3H]leucine was counted. In each experiment, a treated-to-control ratio was calculated. [3H]leucine incorporation was 13 460±660 cpm/well for control myocytes treated with diluent. Each point is mean±SEM (n=4 to 8 wells). C indicates control; A II, Ang II. *P<0.005 and **P<0.0001 vs control cultures treated with diluent, P<0.05 vs TNF-, #P<0.005 vs Ang II. B, Inhibitory effects of BHA on TNF-–induced increase in protein content. TNF- (10 ng/mL), BHA (10 µmol/L), or diluent without TNF- (control) was added to cultured myocytes on culture day 4. After 3-day treatment, protein content was measured. Each point is mean±SEM (n=5 wells). C indicates control. **P<0.0001 vs control cultures treated with diluent, P<0.01 vs TNF-.

Inhibitory Effects of BHA on TNF-–Induced Increase in Protein
Total cell protein also increased significantly in TNF-–treated cells (10 ng/mL) (P<0.0001, control versus TNF-, n=5 dishes), but BHA (10 µmol/L) inhibited this hypertrophic effect (P<0.01, TNF- versus TNF- plus BHA, n=5 dishes) (Figure 5B).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The major new finding of this work is that antioxidants can inhibit TNF-–and Ang II–induced hypertrophy in cultured neonatal rat cardiac myocytes. Our hypothesis that TNF- and Ang II cause hypertrophy via the generation of ROIs is supported by the following observations. First, TNF- and Ang II generated ROIs in a dose-dependent manner in cultured cardiac myocytes. Second, BHA inhibited the enlargement of cardiac myocytes and the increase of amino acid incorporation induced by TNF- and Ang II. Cardiac myocyte hypertrophy is characterized by an enlargement of the myocyte and a gain in protein.^{12 27} Our study shows that BHA can prevent myocyte enlargement and protein increase induced by TNF- and Ang II.

In addition to BHA, other antioxidants such as vitamin E and catalase were also able to inhibit cardiac myocyte enlargement induced by TNF-. Vitamin E can scavenge free radicals (eg, peroxyl radicals and superoxide), quench singlet oxygen, and decrease H₂O₂ production,^{32 33 34} and catalase can decompose ROIs such as hydrogen peroxide (H₂O₂) efficiently.³⁵ Our results support the idea that myocyte hypertrophy is mediated by ROIs, but the precise mechanism by which the ROIs cause hypertrophy remains unknown.

It is well known that Ang II causes hypertrophy of cardiac myocytes,^{14 15} and multiple intracellular pathways in Ang II signaling have been reported. Among the reported effects are activation of protein kinase C,³⁶ extracellular signal-regulated kinase,³⁷ or c-Jun N-terminal kinase^{20 38} ; induction of immediate-early genes^{14 36} ; and elevations in intracellular calcium³⁶ and formation of ROIs.²⁴ In this study, we also showed that Ang II in the same dose as was used in the above-mentioned studies generated ROIs. Further experiments remain to be done to learn the relationships among those mechanisms and the precise mechanisms of Ang II–induced myocyte hypertrophy.

Formation of ROIs can be considered to be one of the mechanisms of cell injury. For example, reperfusion injury in the heart is associated with ROIs generated by reoxygenation. If TNF- and Ang II are persistently present at high concentrations, short-lived ROIs will be produced constantly and will contribute to continued cell damage in the heart. From this point of view, antioxidants may be effective against both hypertrophy and injury induced by ROIs.

In summary, our data showed that ROIs were generated in neonatal rat cardiac myocytes exposed to TNF- and Ang II and that the cardiac myocyte hypertrophy induced by TNF- and Ang II was inhibited by antioxidants such as BHA, vitamin E, and catalase. TNF- and Ang II may cause cardiac myocyte hypertrophy in part via the generation of ROIs.

	Acknowledgments

 
We thank Professor Takuro Murakami, Department of Anatomy, Okayama University Medical School for his continuous encouragement in our work.

Received February 11, 1998; revision received April 7, 1998; accepted April 22, 1998.

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				X. Zheng, D. Lian, A. Wong, M. Bygrave, T. E. Ichim, M. Khoshniat, X. Zhang, H. Sun, T. De Zordo, J. C. Lacefield, et al. Novel Small Interfering RNA-Containing Solution Protecting Donor Organs in Heart Transplantation Circulation, September 22, 2009; 120(12): 1099 - 1107. [Abstract] [Full Text] [PDF]

				K. R. Brunt, M. R. Tsuji, J. H. Lai, R. T. Kinobe, W. Durante, W. C. Claycomb, C. A. Ward, and L. G. Melo Heme Oxygenase-1 Inhibits Pro-Oxidant Induced Hypertrophy in HL-1 Cardiomyocytes Experimental Biology and Medicine, May 1, 2009; 234(5): 582 - 594. [Abstract] [Full Text] [PDF]

				V. W. Dolinsky, A. Y.M. Chan, I. Robillard Frayne, P. E. Light, C. Des Rosiers, and J. R.B. Dyck Resveratrol Prevents the Prohypertrophic Effects of Oxidative Stress on LKB1 Circulation, March 31, 2009; 119(12): 1643 - 1652. [Abstract] [Full Text] [PDF]

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				K. Rivard, P. Paradis, M. Nemer, and C. Fiset Cardiac-specific overexpression of the human type 1 angiotensin II receptor causes delayed repolarization Cardiovasc Res, April 1, 2008; 78(1): 53 - 62. [Abstract] [Full Text] [PDF]

				I. Murtaza, H.-X. Wang, X. Feng, N. Alenina, M. Bader, B. S. Prabhakar, and P.-F. Li Down-regulation of Catalase and Oxidative Modification of Protein Kinase CK2 Lead to the Failure of Apoptosis Repressor with Caspase Recruitment Domain to Inhibit Cardiomyocyte Hypertrophy J. Biol. Chem., March 7, 2008; 283(10): 5996 - 6004. [Abstract] [Full Text] [PDF]

				X.-J. Zou, L. Yang, and S.-L. Yao Propofol Depresses Angiotensin II-Induced Cardiomyocyte Hypertrophy In Vitro Experimental Biology and Medicine, February 1, 2008; 233(2): 200 - 208. [Abstract] [Full Text] [PDF]

				A. Kobayashi, K. Ishikawa, H. Matsumoto, S. Kimura, Y. Kamiyama, and Y. Maruyama Synergetic Antioxidant and Vasodilatory Action of Carbon Monoxide in Angiotensin II Induced Cardiac Hypertrophy Hypertension, December 1, 2007; 50(6): 1040 - 1048. [Abstract] [Full Text] [PDF]

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				S. D. Hingtgen, X. Tian, J. Yang, S. M. Dunlay, A. S. Peek, Y. Wu, R. V. Sharma, J. F. Engelhardt, and R. L. Davisson Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy Physiol Genomics, September 14, 2006; 26(3): 180 - 191. [Abstract] [Full Text] [PDF]

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				V. P.M. van Empel, A. T. Bertrand, R. J. van Oort, R. van der Nagel, M. Engelen, H. V. van Rijen, P. A. Doevendans, H. J. Crijns, S. L. Ackerman, W. Sluiter, et al. EUK-8, a Superoxide Dismutase and Catalase Mimetic, Reduces Cardiac Oxidative Stress and Ameliorates Pressure Overload-Induced Heart Failure in the Harlequin Mouse Mutant J. Am. Coll. Cardiol., August 15, 2006; 48(4): 824 - 832. [Abstract] [Full Text] [PDF]

				C. E. Murdoch, M. Zhang, A. C. Cave, and A. M. Shah NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure Cardiovasc Res, July 15, 2006; 71(2): 208 - 215. [Abstract] [Full Text] [PDF]

				S. Javadov, D. Baetz, V. Rajapurohitam, A. Zeidan, L. A. Kirshenbaum, and M. Karmazyn Antihypertrophic Effect of Na+/H+ Exchanger Isoform 1 Inhibition Is Mediated by Reduced Mitogen-Activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-Derived Reactive Oxygen Species J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1036 - 1043. [Abstract] [Full Text] [PDF]

				A. Planavila, R. Rodriguez-Calvo, A. F. de Arriba, R. M. Sanchez, J. C. Laguna, M. Merlos, and M. Vazquez-Carrera Inhibition of Cardiac Hypertrophy by Triflusal (4-Trifluoromethyl Derivative of Salicylate) and Its Active Metabolite Mol. Pharmacol., April 1, 2006; 69(4): 1174 - 1181. [Abstract] [Full Text] [PDF]

				J. Murali and R. Jayakumar Lymphocyte toxicity of prion fragments. J. Biochem., March 1, 2006; 139(3): 329 - 338. [Abstract] [Full Text] [PDF]

				D. J. Grieve, J. A. Byrne, A. Siva, J. Layland, S. Johar, A. C. Cave, and A. M. Shah Involvement of the Nicotinamide Adenosine Dinucleotide Phosphate Oxidase Isoform Nox2 in Cardiac Contractile Dysfunction Occurring in Response to Pressure Overload J. Am. Coll. Cardiol., February 21, 2006; 47(4): 817 - 826. [Abstract] [Full Text] [PDF]

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				M. Yano, S. Okuda, T. Oda, T. Tokuhisa, H. Tateishi, M. Mochizuki, T. Noma, M. Doi, S. Kobayashi, T. Yamamoto, et al. Correction of Defective Interdomain Interaction Within Ryanodine Receptor by Antioxidant Is a New Therapeutic Strategy Against Heart Failure Circulation, December 6, 2005; 112(23): 3633 - 3643. [Abstract] [Full Text] [PDF]

				N. Kawamura, T. Kubota, S. Kawano, Y. Monden, A. M. Feldman, H. Tsutsui, A. Takeshita, and K. Sunagawa Blockade of NF-{kappa}B improves cardiac function and survival without affecting inflammation in TNF-{alpha}-induced cardiomyopathy Cardiovasc Res, June 1, 2005; 66(3): 520 - 529. [Abstract] [Full Text] [PDF]

				I. Tsujimoto, S. Hikoso, O. Yamaguchi, K. Kashiwase, A. Nakai, T. Takeda, T. Watanabe, M. Taniike, Y. Matsumura, K. Nishida, et al. The Antioxidant Edaravone Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy Hypertension, May 1, 2005; 45(5): 921 - 926. [Abstract] [Full Text] [PDF]

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				G. F. Tomaselli and D. P. Zipes What Causes Sudden Death in Heart Failure? Circ. Res., October 15, 2004; 95(8): 754 - 763. [Abstract] [Full Text] [PDF]

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				F.-P. Xu, M.-S. Chen, Y.-Z. Wang, Q. Yi, S.-B. Lin, A. F. Chen, and J.-D. Luo Leptin Induces Hypertrophy via Endothelin-1-Reactive Oxygen Species Pathway in Cultured Neonatal Rat Cardiomyocytes Circulation, September 7, 2004; 110(10): 1269 - 1275. [Abstract] [Full Text] [PDF]

				K. Sekiguchi, X. Li, M. Coker, M. Flesch, P. M Barger, N. Sivasubramanian, and D. L Mann Cross-regulation between the renin-angiotensin system and inflammatory mediators in cardiac hypertrophy and failure Cardiovasc Res, August 15, 2004; 63(3): 433 - 442. [Abstract] [Full Text] [PDF]

				S. E Hardt and J. Sadoshima Negative regulators of cardiac hypertrophy Cardiovasc Res, August 15, 2004; 63(3): 500 - 509. [Abstract] [Full Text] [PDF]

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				C.-M. Hu, Y.-H. Chen, M.-T. Chiang, and L.-Y. Chau Heme Oxygenase-1 Inhibits Angiotensin II-Induced Cardiac Hypertrophy In Vitro and In Vivo Circulation, July 20, 2004; 110(3): 309 - 316. [Abstract] [Full Text] [PDF]

				M. Nian, P. Lee, N. Khaper, and P. Liu Inflammatory Cytokines and Postmyocardial Infarction Remodeling Circ. Res., June 25, 2004; 94(12): 1543 - 1553. [Abstract] [Full Text] [PDF]

				M. Valgimigli, E. Merli, P. Malagutti, O. Soukhomovskaia, G. Cicchitelli, A. Antelli, D. Canistro, G. Francolini, G. Macri, F. Mastrorilli, et al. Hydroxyl radical generation, levels of tumor necrosis factor-alpha, and progression to heart failure after acute myocardial infarction J. Am. Coll. Cardiol., June 2, 2004; 43(11): 2000 - 2008. [Abstract] [Full Text] [PDF]

				Y.-C. Fu, C.-S. Chi, S.-C. Yin, B. Hwang, Y.-T. Chiu, and S.-L. Hsu Norepinephrine induces apoptosis in neonatal rat cardiomyocytes through a reactive oxygen species-TNF{alpha}-caspase signaling pathway Cardiovasc Res, June 1, 2004; 62(3): 558 - 567. [Abstract] [Full Text] [PDF]

				J. Yoshioka, P. C. Schulze, M. Cupesi, J. D. Sylvan, C. MacGillivray, J. Gannon, H. Huang, and R. T. Lee Thioredoxin-Interacting Protein Controls Cardiac Hypertrophy Through Regulation of Thioredoxin Activity Circulation, June 1, 2004; 109(21): 2581 - 2586. [Abstract] [Full Text] [PDF]

				J. Hokamaki, H. Kawano, M. Yoshimura, H. Soejima, S. Miyamoto, I. Kajiwara, S. Kojima, T. Sakamoto, S. Sugiyama, N. Hirai, et al. Urinary biopyrrins levels are elevated in relation to severity of heart failure J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1880 - 1885. [Abstract] [Full Text] [PDF]

				M. Maytin, D. A. Siwik, M. Ito, L. Xiao, D. B. Sawyer, R. Liao, and W. S. Colucci Pressure Overload-Induced Myocardial Hypertrophy in Mice Does Not Require gp91phox Circulation, March 9, 2004; 109(9): 1168 - 1171. [Abstract] [Full Text] [PDF]

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				J. A. Byrne,*, D. J. Grieve, J. K. Bendall, J.-M. Li, C. Gove, J. D. Lambeth, A. C. Cave, and A. M. Shah Contrasting Roles of NADPH Oxidase Isoforms in Pressure-Overload Versus Angiotensin II-Induced Cardiac Hypertrophy Circ. Res., October 31, 2003; 93(9): 802 - 805. [Abstract] [Full Text] [PDF]

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				A. Warnholtz and T. Munzel The failing human heart: Another battlefield for the NAD(P)H oxidase? J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2172 - 2174. [Full Text] [PDF]

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				A. Sachinidis, B. K. Fleischmann, E. Kolossov, M. Wartenberg, H. Sauer, and J. Hescheler Cardiac specific differentiation of mouse embryonic stem cells Cardiovasc Res, May 1, 2003; 58(2): 278 - 291. [Abstract] [Full Text] [PDF]

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				J. Francis, R. M. Weiss, A. K. Johnson, and R. B. Felder Central mineralocorticoid receptor blockade decreases plasma TNF-alpha after coronary artery ligation in rats Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R328 - R335. [Abstract] [Full Text] [PDF]

				Y. Machida, T. Kubota, N. Kawamura, H. Funakoshi, T. Ide, H. Utsumi, Y. Y. Li, A. M. Feldman, H. Tsutsui, H. Shimokawa, et al. Overexpression of tumor necrosis factor-alpha increases production of hydroxyl radical in murine myocardium Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H449 - H455. [Abstract] [Full Text] [PDF]

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				J. Fukuzawa, J. Nishihira, N. Hasebe, T. Haneda, J. Osaki, T. Saito, T. Nomura, T. Fujino, N. Wakamiya, and K. Kikuchi Contribution of Macrophage Migration Inhibitory Factor to Extracellular Signal-regulated Kinase Activation by Oxidative Stress in Cardiomyocytes J. Biol. Chem., July 5, 2002; 277(28): 24889 - 24895. [Abstract] [Full Text] [PDF]

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				H. Funakoshi, T. Kubota, N. Kawamura, Y. Machida, A. M. Feldman, H. Tsutsui, H. Shimokawa, and A. Takeshita Disruption of Inducible Nitric Oxide Synthase Improves {beta}-Adrenergic Inotropic Responsiveness but Not the Survival of Mice With Cytokine-Induced Cardiomyopathy Circ. Res., May 17, 2002; 90(9): 959 - 965. [Abstract] [Full Text] [PDF]

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				T. Force, S. Haq, H. Kilter, and A. Michael Apoptosis Signal-Regulating Kinase/Nuclear Factor-{kappa}B: A Novel Signaling Pathway Regulates Cardiomyocyte Hypertrophy Circulation, January 29, 2002; 105(4): 402 - 404. [Full Text] [PDF]

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				J. K. Bendall, A. C. Cave, C. Heymes, N. Gall, and A. M. Shah Pivotal Role of a gp91phox-Containing NADPH Oxidase in Angiotensin II-Induced Cardiac Hypertrophy in Mice Circulation, January 22, 2002; 105(3): 293 - 296. [Abstract] [Full Text] [PDF]

				T. Aizawa, N. Ishizaka, S.-I. Usui, N. Ohashi, M. Ohno, and R. Nagai Angiotensin II and Catecholamines Increase Plasma Levels of 8-Epi-Prostaglandin F2{alpha} With Different Pressor Dependencies in Rats Hypertension, January 1, 2002; 39(1): 149 - 154. [Abstract] [Full Text] [PDF]

				M.-W. Hwang, A. Matsumori, Y. Furukawa, K. Ono, M. Okada, A. Iwasaki, M. Hara, T. Miyamoto, M. Touma, and S. Sasayama Neutralization of interleukin-1{beta} in the acute phase of myocardial infarction promotes the progression of left ventricular remodeling J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1546 - 1553. [Abstract] [Full Text] [PDF]

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				S. F. Nagueh, S. J. Stetson, N. M. Lakkis, D. Killip, A. Perez-Verdia, M. L. Entman, W. H. Spencer III, and G. Torre-Amione Decreased Expression of Tumor Necrosis Factor-{{alpha}} and Regression of Hypertrophy After Nonsurgical Septal Reduction Therapy for Patients With Hypertrophic Obstructive Cardiomyopathy Circulation, April 10, 2001; 103(14): 1844 - 1850. [Abstract] [Full Text] [PDF]

				E. Hiraoka, S. Kawashima, T. Takahashi, Y. Rikitake, T. Kitamura, W. Ogawa, and M. Yokoyama TNF-{alpha} induces protein synthesis through PI3-kinase-Akt/PKB pathway in cardiac myocytes Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1861 - H1868. [Abstract] [Full Text] [PDF]

				K. Tanaka, M. Honda, and T. Takabatake Redox regulation of MAPK pathways and cardiac hypertrophy in adult rat cardiac myocyte J. Am. Coll. Cardiol., February 1, 2001; 37(2): 676 - 685. [Abstract] [Full Text] [PDF]

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