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1 Department of Medicine, Houston Veterans Affairs Medical Center, 2 Winters Center for Heart Failure Research, and Section of Infectious Diseases, 3 Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The precise molecular mechanisms responsible for sepsis-induced myocardial dysfunction remain undefined. Toll-like receptor-4 (TLR-4) engages lipopolysaccharide (LPS) and activates signaling pathways leading to the expression of proinflammatory cytokines implicated in myocardial dysfunction. We determined whether TLR-4 was necessary for LPS-induced myocardial dysfunction in vivo. The effects of LPS on left ventricular (LV) function were studied in mice with defective TLR-4 signaling (C3H/HeJ, TLR-4 deficient) and wild-type mice (C3HeB/FeJ). Mice (n = 5/group) were injected with LPS or diluent, and LV function was examined by using two-dimensional echocardiography and conductance catheters. LPS significantly decreased all indexes of LV function in wild-type mice when compared with controls; LV function was not depressed in the LPS-treated TLR-4-deficient mice relative to controls. LPS increased myocardial nitric oxide synthase-2 expression and cGMP only in wild-type mice. This study suggests that TLR-4 mediates the LV dysfunction that occurs in LPS-induced shock. Therefore, TLR-4 might be a therapeutic target for attenuating the effects of LPS on the heart.
innate immunity; endotoxic shock; proinflammatory cytokine; myocardial depression
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE PATHOGENESIS of gram-negative septic shock is believed to result from excessive stimulation of host cells by bacterial lipopolysaccharide (LPS) (1, 15). LPS stimulation leads to the expression and release of a portfolio of proinflammatory cytokines and lipid mediators, which can in turn initiate a chain of events leading to systemic toxicity (20). One of the well-recognized toxic effects of LPS is the development of left ventricular (LV) dysfunction and cardiovascular collapse (16, 17, 25). Although there has been a great deal of progress in terms of understanding how LPS induces myocardial dysfunction, the precise cellular and molecular mechanisms that are responsible for sepsis-induced myocardial dysfunction have not been fully defined.
One of the major advances in terms of our understanding the early
events that are downstream from LPS-mediated signaling has been the
identification of Toll-like receptors (TLRs). Toll is a transmembrane
receptor in Drosophila that is involved in dorsal-ventral patterning in the embryo and in the induction of an antifungal response
in the adult fly (2). Certain TLR family members act as
cell surface receptors for LPS, including Toll-like receptor-2 (TLR-2)
and Toll-like receptor-4 (TLR-4). Importantly, TLR-mediated signaling
has been linked to activation of NF
B/Rel-type transcription factors,
as well as upregulation of proinflammatory cytokines such as tumor
necrosis factor (TNF), interleukin-1
(IL-1), interleukin-6 (IL-6), and nitric oxide (NO). Recent studies have shown that the heart
expresses TLR-2 and TLR-4 mRNA and protein (3, 8), raising
the interesting possibility that TLRs might be responsible for
mediating the deleterious effects of LPS on myocardial function. To
this end, we have recently begun to explore the role of TLR-4-mediated signaling in the adult heart. Thus far, our laboratory and others (3, 8) have shown that TLR-4 was necessary for
upregulating the expression of TNF, IL-1, and NO synthase-2 (NOS2)
in the heart after stimulation with LPS. In the present report, we
extend these observations by examining the role of TLR-4-mediated
signaling in the development of LPS-induced LV dysfunction. The results of this simple study show that TLR-4-mediated signaling is necessary for LPS-induced myocardial dysfunction in the adult mammalian heart.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental Protocol
We examined LV function in the presence and absence of LPS in C3H/HeJ mice (referred to as TLR-4 deficient) that have defective LPS-mediated signaling as the result of a missense mutation (proline
histidine) at codon 712. A genetically similar strain of C3HeB/FeJ mice (referred to as wild-type) with intact TLR-4 receptor-mediated signaling was used as the appropriate control (both from Jackson Laboratory; Bar Harbor, ME). Female TLR-4-deficient and wild-type mice
(age 8-24 wk) were injected intraperitoneally with 5 mg/kg (n = 5 mice/group) or 25 mg/kg (n = 5 mice/group) Escherichia coli LPS (a phenol extract of
serotype 0111:B4, Sigma Chemical; St. Louis, MO). Control mice were
injected with 200 µl of pyrogen-free phosphate-buffered saline (PBS,
GIBCO-BRL; Grand Island, NY). LV structure and function was assessed
6 h after LPS injection in anesthetized animals using
two-dimensional echocardiography and by LV catheterization (see
Hemodynamic assessment of LV function). At the time
of the terminal study, the mice were euthanized with an overdose of
anesthesia, and hearts were excised, rinsed in PBS, snap-frozen in
liquid nitrogen, and stored at 
70°C. Three groups of mice were
studied: diluent (PBS)-treated wild-type (C3HeB/FeJ) control mice,
LPS-treated wild-type (C3HeB/FeJ) mice, and LPS-treated TLR-4-(C3H/HeJ)-deficient mice.
Characterization of LV Structure and Function in TLR-4-Deficient Mice After LPS Challenge
Myocardial histology. Heart tissue from naive (i.e., not stimulated with LPS) wild-type and TLR4-D mice was perfusion fixed in buffered formalin and embedded in paraffin, and the sections were stained with hematoxylin and eosin for routine histological examination and Masson's trichrome staining for myocardial fibrosis (4).
Two-dimensional echocardiography. Mice were anesthetized intraperitoneally with a mixture of ketamine (100 mg/kg), xylazine (2.5 mg/kg), and heparin (5,000 U/kg); additional doses were given as needed. Animals were placed in the supine position under a heat lamp to control body temperature at 37°C. Mice were allowed to breathe spontaneously using 1 l/min of oxygen that was given via a nasal cone. Transthoracic echocardiographic examinations were performed using an Acuson Sequoia Cardiac System equipped with a 15-MHz linear transducer (C256 and 15L8, Acuson; Mountain View, CA). After obtaining a parasternal short-axis view, two-dimensional targeted M-mode tracings were recorded through the anterior and posterior LV walls at a sweep speed of 200 mm/s. Pulsed-wave Doppler signals of the LV outflow tract were obtained from the apical four chamber view and were recorded at a sweep speed of 200 mm/s. All images were digitally acquired and stored for off-line analysis.
Echocardiographic measurements of LV dimensions were recorded at end diastole (EDD) and end systole (ESD) from three consecutive cardiac cycles using the leading edge method (6). End diastole was defined at the peak of the wave from the QRS complex of the electrocardiogram. End systole was defined as the minimum dimension. LV posterior wall thickness was determined at end diastole. LV mass was calculated using the area-length method (24). LV fractional shortening (%FS) was calculated as: %FS = [(EDD ESD)/EDD] × 100. Ejection time (Et) was
determined from the actual pulsed-wave Doppler tracings of LV outflow
by measuring the interval from the beginning of the acceleration to the
end of the deceleration. The myocardial velocity of LV circumferential
shortening (Vcf) was calculated as:
Vcf = [(EDD ESD)/EDD]Et, where Vcf
is in circumferences per second and Et is in seconds.
Hemodynamic assessment of LV function.
LV function was assessed using a 1.4-Fr micro-tipped Millar catheter.
Briefly, the right carotid artery was dissected with the use of a
dissecting microscope (SZ40, Olympus; Tokyo, Japan) and cannulated with
a 1.4-Fr micro-tipped Millar (Millar Instruments; Houston, TX). The
catheter was advanced into the left ventricle under echocardiographic
guidance. The 1.4-Fr high-fidelity micromanometer catheter was
calibrated with a mercury manometer at the beginning of each
experiment. Baseline zero reference was obtained by placing the sensor
in normal saline before insertion. LV pressure (LVP), heart rate, and
the maximal positive and negative first derivative of LV pressure with
respect to time (+dP/dtmax,
dP/dtmax) were then determined. Measurements
of LV function were obtained 6 h after LPS injection in the
wild-type and TLR-4-deficient mice and 6 h after PBS injection in
the control wild-type mice. In preliminary control experiments, we
observed that the heart rates were significantly greater in the
LPS-treated mice than in the diluent-treated mice (
450 vs. 270 beats/min). Given that heart rate modifies isovolumic indexes of
cardiac contractile performance, such as LV dP/dt
(11), the PBS-treated control mice were atrially paced at
450 beats/min during the assessment of LV function. Atrial pacing was
achieved by advancing a 1-Fr bipolar mouse pacing catheter (EP118-2, NuMED, Hopkinton, NY) into the right atrium. Atrial pacing was established using a stimulator (SD9E, Grass Medical Instrument; Quincy, MA).
CVP
(mmHg)]/{[heart rate/60 (s
1)] × AoVTI (cm) × 
[AoD/2 (cm)]2}.
Myocardial NOS2 and cGMP Levels
Given that enhanced formation of NO by NOS2 has been implicated in LPS-induced LV dysfunction in septic shock, we measured NOS2 expression, as well as cGMP levels in the TLR-4-deficient and wild-type mice.NOS2 expression.
NOS2 protein expression was measured in the hearts of wild-type and
TLR-4-deficient mice 6 h after LPS challenge. Hearts were homogenized in 2 ml of ice-cold extraction buffer containing 20 mM
HEPES (pH 7.4), 20 mM -glycerophosphate, 20 mM sodium pyrophosphate, 0.2 mM Na3VO4, 2 mM EDTA, 20 mM sodium
fluoride, 10 mM benzamidine, 1 mM dithiothreitol, 20 ng/ml leupeptin,
0.4 mM Pefabloc SC, and 0.05% Triton X. The homogenate was centrifuged
at 20,000 g for 15 min at 4°C. The supernatant was
collected, and the protein concentration was determined using the
bicinchoninic assay with bovine serum albumin as a standard (Pierce,
Life Science; Rockford, IL). Protein (100 µg/lane) was separated on
7.5% SDS-polyacrylamide gel under denaturing conditions and was
electroblotted onto a nitrocellulose membrane (Bio-Rad; Hercules, CA).
After incubation in 5% skim milk in Tris-buffered saline with 0.05%
Tween at 4°C overnight, the membrane was immunoblotted for 1 h
with rabbit anti-NOS2 antibody (Santa Cruz Biotechnology; Santa Cruz,
CA). The secondary antibody was horseradish peroxidase-conjugated goat anti-rabbit polyclonal antibody. NOS2 expression was detected with
the ECL-Plus Western blotting detection kit (Amersham). The films
were then scanned and the densitometric results analyzed with
Image QuaNT software (Molecular Dynamics; Sunnyvale, CA).
NOS2 immunohistochemistry. To localize the cellular source of NOS2 expression, we performed immunochemistry studies using a rabbit anti-NOS2 antibody (Santa Cruz). Paraffin-embedded sections were used for immunostaining using an immunoenzymatic staining kit (DAKO EnVision+ Systems, Peroxidase, Dako; Carpintera, CA) as recommended by the manufacturer. Counterstaining was performed with hematoxylin, and each immunostained slide was evaluated by light microscopy.
cGMP levels. Tissue cGMP concentrations were measured with an enzyme-linked immunosorbent assay kit (R&D Systems; Minneapolis, MN) according to the manufacturer's suggestions. LV myocardial samples were homogenized in 0.1 N hydrochloric acid and centrifuged at 600 g. Tissue cGMP concentrations are expressed as picomoles of cGMP per milligram protein.
Statistics
Data are expressed as means ± SE. A nonpaired t-test was used to assess baseline differences between wild-type and TLR-4-deficient mice, as well as differences in NOS2 expression between groups. Echocardiographic, hemodynamic data, and biochemical tissue data were compared among the three groups using a one-way analysis of variance (ANOVA); where appropriate, a post hoc analysis of variance testing was performed (Newman-Keuls test). A P value <0.05 was considered statistically significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Characterization of LV Structure and Function in TLR-4-Deficient Mice
Table 1 summarizes the measurements of LV structure and function in the wild-type mice (n = 5) and the TLR-4-deficient mice (n = 5). Although the body weights of the wild-type mice were significantly greater than the TLR-4-deficient mice, there was no significant difference in the baseline heart rate, EDD-to-body weight ratio (EDD/BW), ESD-to-body-weight ratio (ESD/BW), posterior wall thickness (PWTh), or LV mass-to-body weight ratio between the two groups. Furthermore, there was no significant difference in baseline LV function (%FS and Vcf) between the wild-type and TLR-4-deficient mice.
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Representative examples of the histology of the hearts from the
wild-type (Fig. 1, A and
B) and TLR-4-deficient (Fig. 1, D and
E) mice are depicted in Fig. 1. There was no obvious
qualitative difference in the morphological appearance of the
myocardium between any of the groups of mice. Furthermore, there were
no qualitative differences in the amount of fibrous tissue in the
wild-type (Fig. 1C) and TLR-4-deficient (Fig. 1F)
mice.
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Characterization of LV Function in TLR-4-Deficient Mice After LPS Administration
Hemodynamic characterization.
Table 2 summarizes the hemodynamic
measurements in diluent-treated wild-type mice (n = 5)
and in the LPS-treated wild-type mice (n = 5) and the
TLR-4-deficient mice (n = 5); all measurements were
performed 6 h after treatment. As shown there was no significant difference in the heart rate or LV end-diastolic pressure between the
groups of mice. There was, however, a significant (P < 0.05) decrease in LV peak systolic pressure in the LPS-treated
wild-type mice and the TLR-4-deficient mice when compared with
diluent-treated controls. The LV peak systolic pressure was
significantly (P < 0.05) greater in the LPS-treated
TLR-4-deficient mice than in the LPS-treated wild-type mice. As shown
in Table 2, 6 h after LPS challenge, wild-type mice had decreased
MAP and an increase in SVR when compared with LPS-treated
TLR-4-deficient mice.
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Two-dimensional echocardiographic assessment of LV function.
Figure 2 shows representative
echocardiographic pictures of wild-type and TLR-4-deficient mice 6 h after LPS challenge. The salient finding shown by Fig. 2 is that ESD
was greater in LPS-treated wild-type mice (Fig. 2B) when
compared with the LPS-treated TLR-4-deficient mice (Fig.
2D). The results of group data (n = 5/group)
showed that there was a significant (P < 0.05)
increase in ESD in the LPS-treated wild-type mice (2.9 ± 0.1 mm)
compared with diluent-treated wild-type mice (2.6 ± 0.2 mm) or to
LPS-treated TLR-4-deficient mice (2.1 ± 0.1 mm). Importantly, the
increase in ESD in the wild-type mice occurred despite a fall in
systolic pressure in these mice (Table 2), suggesting that the increase
in ESD reflected a decrease in contractility. A second important
finding shown by Fig. 2 is that both the extent of fractional
shortening (Fig. 2E) and the Vcf
(Fig. 2F) were significantly (P < 0.05)
depressed at both doses of LPS (5 and 25 mg/kg) in wild-type mice when
compared with diluent-treated wild-type mice. In contrast, neither
fractional shortening nor Vcf were significantly
(P > 0.05) depressed in the LPS-treated (5 or 25 mg/kg) TLR-4-deficient mice when compared with diluent-treated
wild-type mice.
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Hemodynamic assessment of LV function.
Given that LPS can alter LV afterload, we also assessed LV function
using an index of contractility that is not affected by afterload: LV
dP/dtmax. As shown in Fig.
3A, +LV
dP/dtmax was significantly depressed
(P < 0.05) in the wild-type mice that received LPS (25 mg/kg) when compared with diluent-treated control mice, whereas there
was no significant change (P > 0.05) in
+dP/dtmax in the LPS-treated TLR4-deficient mice
when compared with diluent-treated controls. Furthermore, isovolumic
relaxation (dP/dtmax) was also significantly
decreased (P < 0.05) in the wild-type mice but not in
TLR4-deficient mice treated with LPS (Fig. 3B).
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Myocardial NOS2 Expression and cGMP Levels
Previously we have shown that LPS-induced expression of TNF, IL-1, and NOS2 protein expression is blunted in TLR-4-deficient mice
(3), thus providing a potential mechanistic basis for the
absence of LV dysfunction in the TLR-4-deficient mice. Given that
enhanced formation of NO has been implicated as a mediator of LV
dysfunction in septic shock, we measured NOS2 protein expression and
cGMP (an immediate downstream effector of NO) in LPS (25 mg/kg)-treated wild-type and TLR-4-deficient mice. As shown in Fig.
4A, there was no detectable
NOS2 expression in the ventricles of wild-type and TLR-4-deficient mice
after administration of diluent. However, there was a striking increase
in NOS2 expression in ventricular homogenates of wild-type mice 6 h after LPS administration (Fig. 4, A and B).
This increase in NOS2 expression was not observed in ventricular tissue
from LPS-treated TLR-4-deficient mice. Figure 4, C and
D, shows the localization of NOS2 expression in the
myocardium of LPS-treated wild-type mice. As shown in Fig.
4C, administration of diluent had no effect on NOS2
expression. In contrast, LPS induced a striking increase in NOS2
expression, which in addition to other cells could be localized to
cardiac myocytes (Fig. 4D). Ventricular cGMP concentrations
were also significantly greater in wild-type (P < 0.05) mice than in TLR-4-deficient mice 6 h after LPS challenge
(Fig. 5).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study shows for the first time that TLR-4-mediated signaling
is necessary for the development of LPS-induced myocardial dysfunction
in the adult mammalian heart. Two major lines of evidence support this
statement. First, LPS administration resulted in a significant
depression of ejection phase indexes of LV contractile function (%FS
and Vcf) in wild-type mice, whereas there was no significant change in these parameters in the TLR-4-deficient mice when
compared with diluent-treated control mice (Fig. 2, E and
F). Second, LPS treatment resulted in significantly impaired isovolumetric indexes of LV systolic (peak +dP/dt and peak
developed systolic pressure) and diastolic function (peak
dP/dt) in mice with intact TLR-4 receptors, whereas these
indexes of LV contractility were not different from diluent-treated
control values in the LPS-treated TLR-4-deficient mice (Fig. 3).
Importantly, the observed differences in LPS-induced contractile
dysfunction in the wild-type mice and the TLR-4-deficient mice did not
appear to be secondary to baseline differences in LV structure nor LV
function (Table 1, Fig. 1), insofar as there were no differences
between groups of mice. Moreover, there were no intrinsic LPS-induced
differences in heart rate (Table 2) between the wild-type and
TLR-4-deficient mice following LPS challenge, which would explain the
differences in contractile function. Whereas there were significant
differences in systemic vascular resistance in the TLR-4-deficient and
wild-type mice, the increased systemic vascular resistance observed in
wild-type mice could not have accounted for the depressed
+dP/dt in these mice because this index of contractility is
afterload independent. Taken together the above observations suggest
that the TLR-4 receptor is necessary for activating the downstream
signaling pathways that are responsible for mediating LPS-induced LV dysfunction.
Innate Immunity in the Heart
The immune system has traditionally been divided into innate and adaptive components, each of which has a different role and function in defending the host organism against infectious agents (10). The innate immune response, a preprogrammed (i.e., germ line encoded), nonspecific first-line of defense that is responsible for eliminating and/or containing microorganisms at the site of entrance into the host, is activated by binding of a specific molecular pattern on pathogens (e.g., LPS) to a specific pattern recognition receptor that exists on host cells. Two recent lines of evidence suggest that the adult mammalian myocardium possess a functionally intact innate immune system. First, there is now substantial evidence that the mediators and effectors of the innate immune response, including proinflammatory cytokines, NO, and chemokines are expressed in the adult mammalian heart by cardiac myocytes in response to challenge with classical pathogen-associated molecular patterns, such as LPS and viral particles (12, 18). Second, the heart expresses at least four pattern recognition receptors for pathogen-associated molecular patterns, including CD14, the soluble pattern recognition pattern receptor for LPS (5), as well as TLR-2, TLR-4, and TLR-6 (14). Studies using TLR-2- or TLR-4-deficient mice, as well as in vitro transfection studies, suggest that TLR-4 primarily recognizes LPS and that TLR-2 primarily recognizes gram-positive bacteria and bacterial cell wall components (19, 23). Thus the results of the present study in the heart are consistent with previous reports in nonmyocyte cell types.Although this study did not dissect the TLR-4-mediated signaling
pathways that are responsible for LPS-induced LV dysfunction, we have
shown that LPS-mediated expression of proinflammatory mediators,
including TNF, IL-1, and NO, is significantly blunted and delayed in
the hearts of TLR-4-deficient mice (3). Given that TNF,
IL-1, and NOS2 have been shown to produce myocardial depression in
various models, (7, 9, 22), the decreased expression of
these proinflammatory cytokines may provide one explanation for the
absence of LV dysfunction in the TLR-4-deficient mice. In the present
report, we also show that NOS2 protein expression and cGMP
concentrations are blunted significantly in the TLR-4-deficient mice,
thus providing another potential explanation for the absence of
LPS-induced LV dysfunction in the TLR-4-deficient mice (13, 21). Taken together, these observations suggest that TLR-4 plays an important role in mediating the deleterious effects of LPS on LV
myocardial function. Whether CD14 and/or TLR-2 are also critical in
terms of mediating LPS-induced negative inotropic effects in vivo is
not known at present and is currently under investigation.
In conclusion, this study shows for the first time that innate immune responses that are downstream from TLR-4-mediated signaling are necessary for LPS-induced myocardial dysfunction in the adult mammalian heart. Given that the mortality associated with septic shock continues to remain unacceptably high, it is becoming increasingly important to delineate the molecular mechanisms that contribute to the untoward outcomes in the setting of the systemic sepsis syndrome. In this regard, the results of the present study suggest that disruption of TLR-4-mediated signaling may prove to be an effective strategy for preventing and/or reversing the deleterious effects of LPS on LV structure and function. Accordingly, in future studies it will be important to determine whether disruption of TLR-4-mediated signaling using receptor-based strategies will prevent and/or reverse the deleterious effects of LPS once they are established. Ongoing studies are beginning to address these interesting, if not important questions.
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ACKNOWLEDGEMENTS |
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The authors gratefully acknowledge Mary Soliz for secretarial assistance and Dr. Andrew I. Schafer for past and present support and guidance.
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FOOTNOTES |
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This research was supported by National Institutes of Health Grants P50 HL-O6H and RO1 HL-58081-01, RO1 HL-61543-01, HL-42250-10/10, and RO1 GM-62474-01 and by Deutsche Forshcungsgemeinshaft Grant KN521/1-1 (to P. Kneufermann).
Address for reprint requests and other correspondence: D. L. Mann, Cardiology Research (151C), Houston Veterans Affairs Medical Center, 2002 Holcombe Blvd., Houston, TX 77030 (E-mail: dmann{at}bcm.tmc.edu).
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.
10.1152/ajpheart.00763.2001
Received 24 August 2001; accepted in final form 21 February 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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