| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
increases
production of hydroxyl radical in murine myocardium
1 Department of Cardiovascular Medicine, Graduate School of Medical Sciences, and 2 Department of Biophysics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and 3 Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Transgenic (TG) mice with
cardiac-specific overexpression of tumor necrosis factor-
develop
congestive heart failure with myocardial inflammation. The purpose of
this study was to investigate the effects of tumor necrosis factor-
on reactive oxygen species (ROS) in this mouse model of cardiomyopathy.
Myocardial production of hydroxyl radical detected by electron spin
resonance spectroscopy was significantly increased in TG. Myocardial
expression of Mn-SOD was significantly decreased in TG, whereas that of
Cu,Zn-SOD was unaltered. Myocardial expression of catalase was
unchanged, whereas that of glutathione peroxidase was significantly
increased, in TG. Histological analysis revealed that macrophages and
CD4-positive lymphocytes were increased in TG myocardium. To
investigate whether these infiltrating inflammatory cells were the
source of ROS, we treated TG mice with cyclophosphamide for 7 days.
Although cyclophosphamide significantly suppressed the infiltration of inflammatory cells, it did not diminish the production of hydroxyl radical in TG myocardium. Damaged myocytes, but not infiltrating inflammatory cells, may be the source of ROS in TG.
cytokine; heart failure; reactive oxygen species
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
TUMOR NECROSIS
FACTOR (TNF)- is a proinflammatory cytokine that
exerts a wide range of biological activities. TNF- may play an
important role in the pathogenesis of congestive heart failure for the
following reasons. First, plasma levels of TNF- are elevated in
patients with congestive heart failure (25, 28). Second, the failing human heart expresses a substantial amount of TNF- (13, 27, 35, 38). Third, studies in vitro have shown that TNF- suppresses cardiac contractility (8, 43), provokes myocardial hypertrophy (33, 42), and induces
apoptosis in cardiac myocytes (23). To investigate
the pathophysiological significance of myocardial production of TNF-
in vivo, we (26) made transgenic (TG) mice that
overexpress TNF- specifically in the heart under the control of
-myosin heavy chain promoter. These mice present myocardial
inflammation, ventricular dilatation, and congestive heart failure.
Furthermore, the male mice die younger than the females (10,
20). Treatment with soluble TNF receptors reverses myocardial
inflammation, extracellular matrix remodeling, and ventricular
dysfunction in these mice (24, 30). Several aspects of
these results have since been confirmed by another laboratory
(3). Thus myocardial production of TNF- may play an
important role in the development of congestive heart failure. However,
the mechanisms by which TNF- damages the myocardium remain undefined.
Recent basic and clinical studies indicated that reactive oxygen
species exert versatile effects on cardiovascular function. Reactive
oxygen species can damage various cellular components, including
proteins, lipids, and DNA. It has been demonstrated that reactive
oxygen species are increased in patients with congestive heart
failure (2, 21, 31) as well as in animal models (4, 14, 16, 22). Damaged mitochondria may be the source of reactive oxygen species in the failing myocardium (15, 17). Because TNF- has been shown to exert cytotoxic effects on some types of
tumor cells via the generation of reactive oxygen species (12, 32, 39), it is conceivable that cardiotoxic effects of TNF- may be mediated by increased production of reactive oxygen species. Thus the present study was designed to investigate whether
myocardial production of reactive oxygen species was increased in this
mouse model of cardiomyopathy with cardiac-specific overexpression of TNF-. Changes in antioxidant enzymes and effects of elimination of
inflammatory cells were also evaluated.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Animals.
TG mice with cardiac-specific overexpression of TNF-
(26) and wild-type (WT) littermates were studied. The mice
were 6- to 12-wk-old females unless otherwise mentioned. This
experiment was reviewed by the Committee of the Ethics on Animal
Experiment, Kyushu University Graduate School of Medical Sciences, and
carried out under the control of the Guideline for Animal Experiment, Kyushu University, and the Law (No. 105) and Notification (No. 6) of
the Japanese Government.
Electron spin resonance spectroscopy. We measured myocardial production of hydroxyl radical with electron spin resonance (ESR) spectroscopy as described previously (16, 22). The ESR measurements were performed at room temperature with an X-band (9.45 GHz) ESR spectrometer (JES-RE-1X; JEOL). Immediately after the mice were killed, the heart was perfused with phosphate-buffered saline to remove blood, and left ventricle myocardial samples were freeze-clamped and stored in liquid nitrogen for the subsequent ESR measurements. Samples were homogenized in 50 mM potassium phosphate buffer (pH 7.4) containing protease inhibitors. The homogenates were immediately reacted with hydroxy-TEMPO (0.1 mM) as a spin probe, and its ESR spectra were recorded for up to 5 min at intervals of 30 s. The formation of hydroxyl radical was confirmed by adding dimethylthiourea (DMTU; 50 mM) into the reaction mixture. The contribution of superoxide anion was examined in the presence of SOD (5 U/ml) and catalase (50 U/ml).
Northern blot analysis of antioxidative enzymes. Total RNA was extracted from the left ventricle by an acid guanidinium thiocyanate-phenol-chloroform method (Isogen; Nippon Gene). RNA samples (10 µg) were electrophoresed in a formaldehyde-agarose gel and transferred to a nylon membrane (Hybond-N+, Amersham Pharmacia Biotech). The membrane was then hybridized with 32P-labeled probes as follows: murine Cu,Zn-SOD, nucleotides 267-490 (GenBank M60794 and M35725); murine Mn-SOD, nucleotides 32-743 (GenBank X04972); murine catalase, nucleotides 586-1583 (GenBank L25069); murine glutathione peroxidase (GPx), nucleotides 280-1160 (GenBank X03920); and murine GAPDH. The result of the cDNA hybridization was normalized to that of the GAPDH probe to correct for differences in RNA mass and efficiency of transfer. Data were in turn normalized to the mean of WT samples, arbitrarily set at 1.
Analysis of antioxidative enzyme activities. To prepare protein samples for enzyme activity analysis, the left ventricle was homogenized in 10 vols of ice-cold homogenization buffer (50 mM potassium phosphate buffer, pH 7.4) with a Potter homogenizer. Protein concentrations were determined by the bicinchoninic acid protein assay (Pierce).
Enzyme activity of Cu,Zn-SOD and Mn-SOD was evaluated by nitro blue tetrazolium assay as reported by Beauchamp and Fridovich (1). Briefly, samples containing 50 µg of protein were separated on 7% polyacrylamide gel with electrophoresis. After being soaked in nitro blue tetrazolium, tetramethylethylenediamine, and riboflavin, the gel was placed on a light box. Photochemically generated superoxide anion reduces nitro blue tetrazolium and turns the gel blue except at positions containing Cu,Zn-SOD or Mn-SOD. The upper band indicates the activity of Mn-SOD because the lower band disappeared after cotreatment with 5 mM potassium cyanide, which inhibits Cu,Zn-SOD activity. SOD activity was normalized to the mean of untreated WT samples, arbitrarily set at 1. The peroxidatic activity of catalase was evaluated as reported by Johansson and Borg (19). The method was based on the reaction of the enzyme with methanol in the presence of an optimal concentration of hydrogen peroxide. The formaldehyde produced was measured spectrophotometrically with 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (Purpald) as a chromogen. Catalase activity is expressed as micromoles of formaldehyde per milligram of protein. Activity of GPx was measured with an assay based on the method of Paglia and Valentine (34). The assay was based on the oxidation of reduced glutathione by GPx coupled to the disappearance of NADPH with glutathione reductase. GPx activity is expressed as nanomoles of NADPH oxidized to NADP per minute per milligram of protein, with a molar extinction coefficient for NADPH at 340 nm of 6.22 ×106.Immunohistochemistry. The cryostat sections of the left ventricle were used for immunostaining. The primary antibodies used were as follows: MOMA2, rat anti-mouse macrophage (Serotec MCA519G); L3T4, rat anti-mouse CD4-positive lymphocyte (PharMingen 09001D); and Ly-2, rat anti-mouse CD8-positive lymphocyte (PharMingen 01041D). Positive cells were visualized with an avidin-biotin-peroxidase complex immunoperoxidase technique with diaminobenzidine. Counterstaining was then performed with Mayer's hematoxylin.
Treatment with cyclophosphamide. To suppress the infiltration of inflammatory cells in the myocardium, mice were treated with cyclophosphamide (CYP, 100 mg/kg sc) for 7 days. The mice were killed on day 8 after blood samples were collected for complete blood count analysis. Myocardial infiltration was quantified in hematoxylin and eosin-stained sections of the left ventricle by determination of nuclear density (nuclei/mm2) as described previously (24). All nuclei were counted, including myocytes, fibroblasts, and inflammatory cells.
Statistics. The results are presented as means ± SD. Student's t-test was used to compare each variable between TG and WT mice. One-way ANOVA with Student-Newman-Keuls test was used when more than three groups were compared. Differences were considered to be statistically significant at P < 0.05.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Increased production of hydroxyl radical in TG myocardium.
Myocardial production of hydroxyl radical was evaluated by ESR
spectroscopy with hydroxy-TEMPO as a spin probe (16). The intensity of ESR signals declined more rapidly in TG than WT. A linear
relation was observed in the semilogarithmic plot of peak signal
intensity vs. time (Fig. 1A).
The rate of signal decay, calculated from the slope of this line, has
been shown to reflect the concentration of hydroxyl radical in the
reaction mixture (16). As summarized in Fig.
1B, the rate of signal decay was significantly higher in TG
than WT (0.0693 ± 0.0047 vs. 0.0450 ± 0.0026 min
1; P < 0.001). The hydroxyl radical
scavenger DMTU did not affect the slope in WT, whereas it significantly
decreased the signal decay rate in TG. Because this increase was
abolished by SOD and catalase as well, most of the hydroxyl radical
produced in the myocardium was likely derived from superoxide anion.
|
|
Inhibition of infiltrating cells by CYP.
TG hearts were characterized by a marked infiltration of inflammatory
cells in the myocardium (26). Immunohistochemical analysis
revealed that most of the cells were macrophages and CD4-positive
lymphocytes (Fig. 3). Polymorphonuclear
granulocytes were rarely seen.
|
|
|
|
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
In the present study, we demonstrated that production of hydroxyl
radical was increased in TG myocardium, where the expression and
activity of Mn-SOD were downregulated. Because the inhibition of
infiltration of inflammatory cells did not reduce the production of
hydroxyl radical, damaged myocytes may be the major source of reactive
oxygen species in this mouse model of cardiomyopathy due to
overexpression of TNF-.
We recently demonstrated (16) that ESR spectroscopy with hydroxy-TEMPO is a reliable method to estimate myocardial production of hydroxyl radical. Hydroxy-TEMPO is a stable nitroxide radical that can be easily detected by ESR spectroscopy. Nitroxides are reduced by biological reductants into nonparamagnetic hydroxylamine compounds, which are ESR silent. Therefore, the decay of hydroxy-TEMPO can provide a direct method to assess the generation of reactive oxygen species within biological tissues. Our in vitro validation studies (16) demonstrated that the acceleration of the rate of signal decay is proportional to the amount of hydroxyl radical in the reaction mixture. However, in living tissues, paramagnetism of hydroxy-TEMPO can be lost not only by hydroxyl radical but also by various mechanisms, including reductants in the cytosol, one-electron reduction due to enzymatic processes, and mitochondrial electron flow (6). Therefore, to distinguish the effects of hydroxyl radical from those of other factors, a specific hydroxyl radical scavenger, DMTU, was used in the present study. Although DMTU did not alter the ESR signal in WT myocardium, it significantly reduced the signal decay rate in TG samples, suggesting that the enhanced decay rate reflects the increased production of hydroxyl radical in TG myocardium.
Male TG mice have higher mortality than females, with earlier development of cardiac dysfunction (10, 20). The survival curve of male TG mice starts to decline by 6 weeks of age, and the 6-mo survival rate of male and female TG mice is 52% and 89%, respectively (20). In the present study, we studied 6- to 12-wk-old TG females because of their availability. Because male TG mice died earlier of congestive heart failure, we were not able to obtain a large enough number of samples from male TG in the present analysis. Our recent study (11) demonstrated that both left ventricular fractional shortening and positive maximum rate of rise of pressure are significantly decreased in these young TG females, although neither left ventricular dilatation nor elevation of end-diastolic pressure was observed. In the present study, we demonstrated that production of hydroxyl radical was significantly increased in these young TG females, suggesting that increased production of reactive oxygen species may be an initial event triggering cardiomyopathic dysfunction rather than an end stage-specific mechanism contributing to late cardiomyopathic dysfunction. Because we only studied TG females, it remains to be elucidated whether earlier development of congestive heart failure in TG males is associated with a higher degree of hydroxyl radical production.
The myocardium has a variety of endogenous antioxidant mechanisms.
Among these, the dismutation of superoxide anion by cytosolic Cu,Zn-SOD
or mitochondrial Mn-SOD as well as the degradation of hydrogen peroxide
by catalase or GPx may play an important role (5). TNF-
was reported to upregulate Mn-SOD without affecting Cu,Zn-SOD,
catalase, or GPx in a human lung carcinoma cell line (40).
It was also shown that TNF- protects the heart from
ischemia-reperfusion injury via induction of Mn-SOD
(7, 41). Therefore, we had expected that Mn-SOD was
upregulated in TG myocardium. However, the results were the
opposite: Mn-SOD was significantly downregulated, whereas GPx was
significantly upregulated with no changes in Cu,Zn-SOD or catalase
expression. These results indicate that the chronic effects of TNF-
on antioxidant enzymes may differ from those of acute exposure.
TG myocardium was characterized by a marked increase in infiltrating
inflammatory cells (26). Immunohistochemical analysis revealed that most of the infiltrating cells were macrophages and
CD4-positive lymphocytes. Polymorphonuclear granulocytes were rarely
seen. To distinguish whether reactive oxygen species in TG myocardium
were derived from inflammatory infiltrating cells or cardiac myocytes,
we used CYP in the present study. Treatment with CYP caused leukopenia
and significantly diminished the number of infiltrating inflammatory
cells in TG myocardium. However, increased myocardial production of
hydroxyl radical detected by ESR spectroscopy was unaltered.
Furthermore, neither Mn-SOD nor GPx was affected. Thus hydroxyl radical
seems to be produced predominantly by cardiac myocytes, where Mn-SOD is
downregulated and GPx is upregulated. Although we cannot exclude the
possibility that infiltrating inflammatory cells may play an important
role in the pathogenesis of cardiac dysfunction, they are not the
primary source of reactive oxygen species in this mouse model of
cardiomyopathy with TNF- overexpression.
Superoxide anion is formed by one-electron reduction of molecular
oxygen by various enzymatic electron transport systems, including NADPH
oxidase, xanthine oxidase, cyclooxygenase, nitric oxide synthase, and
mitochondrial complexes I and II (36). TNF- activates
NADPH oxidase in endothelial cells (9). Thus it is possible that activated NADPH oxidase might be a source of superoxide anion in TG myocardium. Furthermore, our recent study (17)
suggests that mitochondrial electron transport complex I may be the
major source of superoxide anion in the failing myocardium. Indeed, mitochondrial structure and function in TG myocardium are impaired with
reduced mitochondrial DNA repair activity (29). We also demonstrated (37) that TNF- decreases the copy number
of mitochondrial DNA via production of reactive oxygen species. In
addition, mitochondrial DNA damage associated with increased production
of reactive oxygen species was observed in a murine model of myocardial
infarction (15), where expression of TNF- is increased
(18). Therefore, an intimate link among TNF-, reactive
oxygen species, mitochondria DNA damage, and defects in the electron
transport function, which may lead to an additional generation of
reactive oxygen species, may play an important role in the development
and progression of myocardial dysfunction with TNF- overexpression.
Further studies are required to examine whether antioxidant therapy
prevents TG mice from developing heart failure.
| |
ACKNOWLEDGEMENTS |
|---|
A part of this study was conducted in the Kyushu University Station for Collaborative Research.
| |
FOOTNOTES |
|---|
This study was supported by a grant from the Study Group of Molecular Cardiology, by a grant from Kowa Life Science Foundation, and by a grant-in-aid for Scientific Research from the Japan Society for the Promotion of Science (C13670719).
Address for reprint requests and other correspondence: T. Kubota, Dept. of Cardiovascular Medicine, Kyushu Univ. Graduate School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan (E-mail: kubotat{at}cardiol.med.kyushu-u.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published October 17, 2002;10.1152/ajpheart.00581.2002
Received 12 July 2002; accepted in final form 4 October 2002.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Beauchamp, C,
and
Fridovich I.
Superoxide dismutase: improved assays and an assay applicable to acrylamide gels.
Anal Biochem
44:
276-287,
1971[ISI][Medline].
2.
Belch, JJ,
Bridges AB,
Scott N,
and
Chopra M.
Oxygen free radicals and congestive heart failure.
Br Heart J
65:
245-248,
1991
3.
Bryant, D,
Becker L,
Richardson J,
Shelton J,
Franco F,
Peshock R,
Thompson M,
and
Giroir B.
Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-.
Circulation
97:
1375-1381,
1998
4.
Dhalla, AK,
Hill MF,
and
Singal PK.
Role of oxidative stress in transition of hypertrophy to heart failure.
J Am Coll Cardiol
28:
506-514,
1996[Abstract].
5.
Dieterich, S,
Bieligk U,
Beulich K,
Hasenfuss G,
and
Prestle J.
Gene expression of antioxidative enzymes in the human heart: increased expression of catalase in the end-stage failing heart.
Circulation
101:
33-39,
2000
6.
Dikalov, S,
Skatchkov M,
and
Bassenge E.
Spin trapping of superoxide radicals and peroxynitrite by 1-hydroxy-3-carboxy-pyrrolidine and 1-hydroxy-2,2,6, 6-tetramethyl-4-oxo-piperidine and the stability of corresponding nitroxyl radicals towards biological reductants.
Biochem Biophys Res Commun
231:
701-704,
1997[ISI][Medline].
7.
Eddy, LJ,
Goeddel DV,
and
Wong GH.
Tumor necrosis factor- pretreatment is protective in a rat model of myocardial ischemia-reperfusion injury.
Biochem Biophys Res Commun
184:
1056-1059,
1992[ISI][Medline].
8.
Finkel, MS,
Oddis CV,
Jacob TD,
Watkins SC,
Hattler BG,
and
Simmons RL.
Negative inotropic effects of cytokines on the heart mediated by nitric oxide.
Science
257:
387-389,
1992
9.
Frey, RS,
Rahman A,
Kefer JC,
Minshall RD,
and
Malik AB.
PKC
regulates TNF--induced activation of NADPH oxidase in endothelial cells.
Circ Res
90:
1012-1019,
2002
10.
Funakoshi, H,
Kubota T,
Kawamura N,
Machida Y,
Feldman AM,
Tsutsui H,
Shimokawa H,
and
Takeshita A.
Disruption of inducible nitric oxide synthase improves 
-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy.
Circ Res
90:
959-965,
2002
11.
Funakoshi, H,
Kubota T,
Machida Y,
Kawamura N,
Feldman AM,
Tsutsui H,
Shimokawa H,
and
Takeshita A.
Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-.
Am J Physiol Heart Circ Physiol
282:
H2159-H2166,
2002
12.
Goossens, V,
Grooten J,
De Vos K,
and
Fiers W.
Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity.
Proc Natl Acad Sci USA
92:
8115-8119,
1995
13.
Habib, FM,
Springall DR,
Davies GJ,
Oakley CM,
Yacoub MH,
and
Polak JM.
Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy.
Lancet
347:
1151-1155,
1996[ISI][Medline].
14.
Hill, MF,
and
Singal PK.
Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats.
Am J Pathol
148:
291-300,
1996[Abstract].
15.
Ide, T,
Tsutsui H,
Hayashidani S,
Kang D,
Suematsu N,
Nakamura K,
Utsumi H,
Hamasaki N,
and
Takeshita A.
Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction.
Circ Res
88:
529-535,
2001
16.
Ide, T,
Tsutsui H,
Kinugawa S,
Suematsu N,
Hayashidani S,
Ichikawa K,
Utsumi H,
Machida Y,
Egashira K,
and
Takeshita A.
Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium.
Circ Res
86:
152-157,
2000
17.
Ide, T,
Tsutsui H,
Kinugawa S,
Utsumi H,
Kang D,
Hattori N,
Uchida K,
Arimura K,
Egashira K,
and
Takeshita A.
Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium.
Circ Res
85:
357-363,
1999
18.
Irwin, MW,
Mak S,
Mann DL,
Qu R,
Penninger JM,
Yan A,
Dawood F,
Wen WH,
Shou Z,
and
Liu P.
Tissue expression and immunolocalization of tumor necrosis factor- in postinfarction dysfunctional myocardium.
Circulation
99:
1492-1498,
1999
19.
Johansson, LH,
and
Borg LA.
A spectrophotometric method for determination of catalase activity in small tissue samples.
Anal Biochem
174:
331-336,
1988[ISI][Medline].
20.
Kadokami, T,
McTiernan CF,
Kubota T,
Frye CS,
and
Feldman AM.
Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression.
J Clin Invest
106:
589-597,
2000[ISI][Medline].
21.
Keith, M,
Geranmayegan A,
Sole MJ,
Kurian R,
Robinson A,
Omran AS,
and
Jeejeebhoy KN.
Increased oxidative stress in patients with congestive heart failure.
J Am Coll Cardiol
31:
1352-1356,
1998
22.
Kinugawa, S,
Tsutsui H,
Hayashidani S,
Ide T,
Suematsu N,
Satoh S,
Utsumi H,
and
Takeshita A.
Treatment with dimethylthiourea prevents left ventricular remodeling and failure after experimental myocardial infarction in mice: role of oxidative stress.
Circ Res
87:
392-398,
2000
23.
Krown, KA,
Page MT,
Nguyen C,
Zechner D,
Gutierrez V,
Comstock KL,
Glembotski CC,
Quintana PJ,
and
Sabbadini RA.
Tumor necrosis factor -induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death.
J Clin Invest
98:
2854-2865,
1996[ISI][Medline].
24.
Kubota, T,
Bounoutas GS,
Miyagishima M,
Kadokami T,
Sanders VJ,
Bruton C,
Robbins PD,
McTiernan CF,
and
Feldman AM.
Soluble tumor necrosis factor receptor abrogates myocardial inflammation but not hypertrophy in cytokine-induced cardiomyopathy.
Circulation
101:
2518-2525,
2000
25.
Kubota, T,
McNamara DM,
Wang JJ,
Trost M,
McTiernan CF,
Mann DL,
and
Feldman AM.
Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. VEST Investigators for TNF Genotype Analysis. Vesnarinone Survival Trial.
Circulation
97:
2499-2501,
1998
26.
Kubota, T,
McTiernan CF,
Frye CS,
Slawson SE,
Lemster BH,
Koretsky AP,
Demetris AJ,
and
Feldman AM.
Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-.
Circ Res
81:
627-635,
1997
27.
Kubota, T,
Miyagishima M,
Alvarez RJ,
Kormos R,
Rosenblum WD,
Demetris AJ,
Semigran MJ,
Dec GW,
Holubkov R,
McTiernan CF,
Mann DL,
Feldman AM,
and
McNamara DM.
Expression of proinflammatory cytokines in the failing human heart: comparison of recent-onset and end-stage congestive heart failure.
J Heart Lung Transplant
19:
819-824,
2000[ISI][Medline].
28.
Levine, B,
Kalman J,
Mayer L,
Fillit HM,
and
Packer M.
Elevated circulating levels of tumor necrosis factor in severe chronic heart failure.
N Engl J Med
323:
236-241,
1990[Abstract].
29.
Li, YY,
Chen D,
Watkins SC,
and
Feldman AM.
Mitochondrial abnormalities in tumor necrosis factor--induced heart failure are associated with impaired DNA repair activity.
Circulation
104:
2492-2497,
2001
30.
Li, YY,
Feng YQ,
Kadokami T,
McTiernan CF,
Draviam R,
Watkins SC,
and
Feldman AM.
Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor can be modulated by anti-tumor necrosis factor therapy.
Proc Natl Acad Sci USA
97:
12746-12751,
2000
31.
Mallat, Z,
Philip I,
Lebret M,
Chatel D,
Maclouf J,
and
Tedgui A.
Elevated levels of 8-iso-prostaglandin F2 in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure.
Circulation
97:
1536-1539,
1998
32.
Matthews, N,
Neale ML,
Jackson SK,
and
Stark JM.
Tumour cell killing by tumour necrosis factor: inhibition by anaerobic conditions, free-radical scavengers and inhibitors of arachidonate metabolism.
Immunology
62:
153-155,
1987[ISI][Medline].
33.
Nakamura, K,
Fushimi K,
Kouchi H,
Mihara K,
Miyazaki M,
Ohe T,
and
Namba M.
Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor- and angiotensin II.
Circulation
98:
794-799,
1998
34.
Paglia, DE,
and
Valentine WN.
Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase.
J Lab Clin Med
70:
158-169,
1967[ISI][Medline].
35.
Satoh, M,
Nakamura M,
Tamura G,
Makita S,
Segawa I,
Tashiro A,
Satodate R,
and
Hiramori K.
Inducible nitric oxide synthase and tumor necrosis factor- in myocardium in human dilated cardiomyopathy.
J Am Coll Cardiol
29:
716-724,
1997[Abstract].
36.
Sorescu, D,
and
Griendling KK.
Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure.
Congest Heart Fail
8:
132-140,
2002[Medline].
37.
Suematsu, N,
Tsutsui H,
Wen JW,
Hayashidani S,
Shiomi T,
Ikeuchi M,
and
Takeshita A.
Oxidative stress mediates tumor necrosis factor--induced mitochondrial DNA damage in cardiac myocytes (Abstract).
Circulation
66:
I-574,
2002.
38.
Torre-Amione, G,
Kapadia S,
Lee J,
Durand JB,
Bies RD,
Young JB,
and
Mann DL.
Tumor necrosis factor- and tumor necrosis factor receptors in the failing human heart.
Circulation
93:
704-711,
1996
39.
Wong, GH,
Elwell JH,
Oberley LW,
and
Goeddel DV.
Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor.
Cell
58:
923-931,
1989[ISI][Medline].
40.
Wong, GH,
and
Goeddel DV.
Induction of manganous superoxide dismutase by tumor necrosis factor: possible protective mechanism.
Science
242:
941-944,
1988
41.
Yamashita, N,
Hoshida S,
Otsu K,
Asahi M,
Kuzuya T,
and
Hori M.
Exercise provides direct biphasic cardioprotection via manganese superoxide dismutase activation.
J Exp Med
189:
1699-1706,
1999
42.
Yokoyama, T,
Nakano M,
Bendnarczyk JL,
McIntyre BW,
Entman M,
and
Mann DL.
Tumor necrosis factor- provokes a hypertrophic growth response in adult cardiac myocytes.
Circulation
95:
1247-1252,
1997
43.
Yokoyama, T,
Vaca L,
Rossen RD,
Durante W,
Hazarika P,
and
Mann DL.
Cellular basis for the negative inotropic effects of tumor necrosis factor- in the adult mammalian heart.
J Clin Invest
92:
2303-2312,
1993[ISI][Medline].
This article has been cited by other articles:
|
|
 |
|
  A. Takaki, K. Morikawa, M. Tsutsui, Y. Murayama, E. Tekes, H. Yamagishi, J. Ohashi, T. Yada, N. Yanagihara, and H. Shimokawa Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice J. Exp. Med., August 11, 2008; (2008) jem.20080106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Funakoshi, L. C. Zacharia, Z. Tang, J. Zhang, L. L. Lee, J. C. Good, D. E. Herrmann, Y. Higuchi, W. J. Koch, E. K. Jackson, et al. A1 Adenosine Receptor Upregulation Accompanies Decreasing Myocardial Adenosine Levels in Mice With Left Ventricular Dysfunction Circulation, May 1, 2007; 115(17): 2307 - 2315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Petkova-Kirova, E. Gursoy, H. Mehdi, C. F. McTiernan, B. London, and G. Salama Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-{alpha} Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2098 - H2107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. Cheranov and J. H. Jaggar TNF-{alpha} dilates cerebral arteries via NAD(P)H oxidase-dependent Ca2+ spark activation Am J Physiol Cell Physiol, April 1, 2006; 290(4): C964 - C971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Higuchi, T. O. Chan, M. A. Brown, J. Zhang, B. R. DeGeorge Jr., H. Funakoshi, G. Gibson, C. F. McTiernan, T. Kubota, W. K. Jones, et al. Cardioprotection afforded by NF-{kappa}B ablation is associated with activation of Akt in mice overexpressing TNF-{alpha} Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H590 - H598. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nimata, T.-a. Okabe, M. Hattori, Z. Yuan, K. Shioji, and C. Kishimoto MCI-186 (edaravone), a novel free radical scavenger, protects against acute autoimmune myocarditis in rats Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2514 - H2518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Matsusaka, M. Ikeuchi, S. Matsushima, T. Ide, T. Kubota, A. M. Feldman, A. Takeshita, K. Sunagawa, and H. Tsutsui Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1858 - H1864. [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]
|
|
|
|
|
|
G. W. Moe, J. Marin-Garcia, A. Konig, M. Goldenthal, X. Lu, and Q. Feng In vivo TNF-{alpha} inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1813 - H1820. [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]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
).
B: CD4-positive lymphocytes. C: CD8-positive
lymphocytes. Values are means ± SD. *P < 0.005 vs. WT.
