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Departments of 1 Medicine (Molecular Cardiology), 2 Cell Biology, and 5 Pathology, Albert Einstein College of Medicine, Bronx, New York 10461; 3 Division of Cardiovascular Research, St. Elizabeth's Medical Center, Boston, Massachusetts 02135; and 4 Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Fas is a widely
expressed cell surface receptor that can initiate apoptosis
when activated by its ligand (FasL). Whereas Fas abundance on cardiac
myocytes increases in response to multiple pathological stimuli, direct
evidence supporting its role in the pathogenesis of heart disease is
lacking. Moreover, controversy exists even as to whether Fas activation
induces apoptosis in cardiac myocytes. In this study, we show
that adenoviral overexpression of FasL, but not 
-galactosidase,
results in marked apoptosis both in cultures of primary
neonatal cardiac myocytes and in the myocardium of intact adult rats.
Myocyte killing by FasL is a specific event, because it does not occur
in lpr (lymphoproliferative) mice that lack functional Fas.
To assess the contribution of the Fas pathway to myocardial infarction
(MI) in vivo, lpr mice were subjected to 30 min of
ischemia followed by 24 h of reperfusion. Compared with
wild-type mice, lpr mice exhibited infarcts that were 62.3%
smaller with 63.8% less myocyte apoptosis. These data provide
direct evidence that activation of Fas can induce apoptosis in
cardiac myocytes and that Fas is a critical mediator of MI due to
ischemia-reperfusion in vivo.
apoptosis; death receptor pathway; genetically altered mice
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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CARDIAC MYOCYTES undergo apoptosis in a wide variety of pathophysiological situations, including ischemia (6, 14, 25, 44), ischemia-reperfusion (8, 14, 16), and hemodynamic overload and heart failure (33, 41, 51). These observations suggest that apoptosis may play a role in the pathogenesis of heart disease. In the case of ischemia-reperfusion, this possibility is supported by studies in which inhibition of apoptosis by a variety of pharmacological and genetic approaches results in smaller infarctions (7-9, 21, 36, 58). Whereas these experiments are important in that they demonstrate a causal role for apoptosis in myocardial infarction (MI), they provide relatively limited information about the pathways that mediate cardiac myocyte apoptosis in vivo.
Apoptosis is mediated by two central pathways. In the mitochondrial pathway (18), diverse stimuli, including nutrient and growth/survival factor deprivation, hypoxia, and oxidative stress, stimulate the translocation of cytochrome c from the mitochondrial intermembrane space and inner membrane to the cytoplasm. Cytochrome c, along with dATP, which is already present in the cytoplasm, then binds to and stimulates the oligomerization of Apaf-1 and the subsequent recruitment and activation of procaspase-9. This leads to the activation of downstream procaspases-3, -6, and -7, proteolysis of specific cellular substrates and cell death. In contrast, the death receptor pathway (2) involves the binding of soluble or cell membrane-bound ligands to cell surface receptors such as Fas and tumor necrosis factor receptor 1 (TNFR1). In the case of Fas, trimeric Fas ligand (FasL), an integral membrane protein, binds to a Fas trimer. This is presumed to induce a conformational change in Fas that enables its cytoplasmic tail to recruit Fas-associated death domain protein (FADD) through interactions involving death domains in both molecules. FADD, in turn, recruits procaspase-8 through homotypic interactions involving death effector motifs. The approximation of procaspase-8 stimulates its autoactivation, following which caspase-8 activates downstream caspases and induces apoptosis. There is cross talk between the death receptor and mitochondrial pathways as caspase-8 cleaves BID, the carboxyl fragment of which translocates to the mitochondria and stimulates cytochrome c release (32, 34).
Recent work has shown that the mitochondrial pathway is activated in cardiac myocytes in response to metabolic stress, hypoxia, and reoxygenation (5, 11, 26, 35). In addition, the mitochondrial pathway is important in cardiac myocyte apoptosis because its disruption by transgenic overexpression of Bcl-2 (7, 9) or dominant negative procaspase-9 (42) markedly reduces infarct size during ischemia-reperfusion in vivo. In contrast, the role of the death receptor pathway in cardiac myocyte apoptosis is less well understood. Although Fas signaling has been implicated in cardiac hypertrophy (3, 38) and calcium signaling (13), its role in cardiac myocyte apoptosis has been less clear. Neonatal and adult cardiac myocytes are killed relatively inefficiently by FasL (55), unless costimulated by doxorubicin (56) or hypoxia (57). Moreover, mice treated systemically with an activating Fas antibody die from massive hepatocyte apoptosis but exhibit no cardiac pathology (40). These observations raise the possibility that Fas activation may not induce apoptosis efficiently in cardiac myocytes. Other observations, however, suggest that the Fas death pathway is functional in these cells. For example, interference of Fas signaling with neutralizing FasL antibodies and in lpr mice that lack Fas (1) decreases cardiac myocyte apoptosis in animal models of doxorubicin toxicity (37) and in isolated perfused hearts subjected to ischemia-reperfusion (23). In addition, the abundance of Fas in the heart increases in response to a variety of insults (23, 25, 37, 50, 55, 59). These data suggest that the Fas-mediated apoptosis may be important in myocardial disease.
Accordingly, the objectives of this study were to test directly whether Fas activation kills cardiac myocytes and, if so, whether this pathway contributes to both myocyte apoptosis and MI following ischemia-reperfusion in vivo. Our data indicate that the Fas death pathway is indeed functional in cardiac myocytes and critical for myocardial damage due to ischemia-reperfusion in vivo.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Reagents and animals. Chemicals were purchased from Sigma Chemical (St. Louis, MO) unless otherwise noted. Six- to eight-week-old C57Bl/6J, MRL/MpJ, and MRL/MpJ-Faslpr male mice were purchased from Jackson Laboratories (Bar Harbor, ME). One-day-old neonatal Sprague-Dawley rat pups were obtained from Taconic Farms (Germantown, NY). Six- to eight-week-old female Wistar rats were purchased from Charles River Laboratories (Wilmington, MA). All experimental protocols were approved by the review board of the Animal Institute of the Albert Einstein College of Medicine.
Primary cultures of neonatal rat cardiac myocytes and adenoviral
infections.
Primary cardiac myocyte cultures were prepared from 1-day-old rat pups
as previously described (5), except that cells were plated
at a density of 380 cells/mm2. Recombinant adenoviruses
encoding murine FasL (AdFasL) and -galactosidase (Ad-gal) under
the control of the cytomegalovirus promoter have been described
previously (45). Approximately 24 h after being plated, cardiac myocytes were infected with the indicated adenovirus at
multiplicity of infection of 200 plaque forming units (pfu)/cell. This
concentration was chosen because infection with Ad-gal at this
multiplicity of infection resulted in transduction of 98-100% of
cells with no toxicity. Cells were harvested for ladder assays 48 h after infection.
DNA ladder assay. This assay was performed on floating and adherent cells as previously described (5).
Direct cardiac injection of adenoviruses.
These were performed as described previously (27). The
injectate for rats consisted of 50 µl of phospate-buffered saline containing a total of 7 × 107 pfu of the virus. This
was delivered as a single injection into the anterolateral and apical
aspect of the left ventricle through a 27-gauge needle attached to a
Hamilton syringe. Experimental animals received a combination of 6 × 107 pfu of AdFasL and 1 × 107 pfu of
Ad-gal, the latter to identify the area of injection. Controls
received 7 × 107 pfu of Ad-gal. Mouse hearts were
injected in the same way except that 30-gauge needles were used and the
injectate consisted of 15 µl. Animals were euthanized 48 h after injection.
Immunohistochemistry for FasL. Cryosections (5 µm thick) were fixed in paraformaldehyde. Biotin-conjugated primary antibody (1:100, clone MFL3, Pharmingen, San Diego, CA; or 1:100, clone Kay10; Pharmingen), which recognizes C57BL/6J mouse FasL, was used, followed by horseradish peroxidase-conjugated streptavidin (BioGenex Laboratories; San Ramon, CA) and AEC chromagen (BioGenex Laboratories). Sections were counter-stained with Meyer's hematoxylin.
TUNEL assay.
Deoxynucleotidlytransferase-mediated dUTP nick end labeling
(TUNEL) was performed on 5-µm frozen sections. The area of the injection was first identified by staining serial sections for -galactosidase, which was expressed by the coinjected Ad-gal. TUNEL was performed with the TACS 2-terminal deoxynucleotidyl transferase Blue or the Fluorescent Apoptosis Detection Kit
(Trevigen; Gaithersburg, MD) according to the manufacturer's
recommendations utilizing 1-h labeling reaction in the presence
of Mn2+. Sections stained with the TACS2 Blue
reagent were counterstained with eosin, whereas fluorescent
sections were counterstained with 1 µg/ml
4',6-diamidino-2-phenylindole (DAPI). Only cells with clear striations
were scored as cardiac myocytes.
Quantitation of TUNEL-positive cells. An apical and a midventricular section taken from the same level of each of the hearts were quantitated by collecting images with an Olympus IX70 CCD digital camera (Roper Scientific; Tuscon, AZ). The left ventricular free wall was demarcated using IPLab (Scanlytics; Vienna, VA) and its area (µm2) calculated by Excel (Microsoft; Redmond, WA). The total number of nuclei per squared micrometer, as determined by staining with DAPI, was assessed in four 10-µm2 sections and averaged. From this density and the area of the left ventricle, the total number of nuclei in the entire left ventricular free wall was calculated. The total number of TUNEL-positive nuclei in cells with clear striations was counted directly over the entire left ventricular free wall (fluorescein). The percentage of TUNEL-positive myocyte nuclei per total nuclei was calculated by dividing the latter by the former and multiplying by 100. The results for the apical and midventricular sections were averaged.
Myocardial ischemia-reperfusion model and infarct size assessment. MRL/MpJ and MRL/MpJ-Faslpr mice were subjected to 30 min of ischemia and 24 h of reperfusion in vivo (19) following which infarcts were quantitated (24) as previously described.
Statistical analysis. Results are expressed as means ± SE. Groups were compared using one-way ANOVA with Tukey's posttest. P < 0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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FasL induces apoptosis in cultured neonatal cardiac
myocytes.
We had previously determined that all components of the Fas pathway
(FasL, Fas, FADD, and procaspase-8) are expressed in the adult heart
(not shown). To test directly whether activation of this pathway can
induce apoptosis in heart muscle cells, primary cultures of
neonatal rat cardiac myocytes were infected with recombinant AdFasL or
Ad-gal. Microscopic examination of DAPI-stained cells in plates
infected with AdFasL showed the development of classic apoptotic
changes consisting of cytoplasmic shrinkage, nuclear condensation, and
detachment of the cells from the plate. In contrast, cells on plates
infected with Ad-gal appeared relatively normal (not shown). DNA
ladder assays were performed on lysates from adherent and floating
cells harvested 48 h later. DNA was intact in lysates from
uninfected plates (Fig. 1, lane
1) and plates infected with
Ad-gal (Fig. 1, lanes 4 and 5). In contrast,
DNA from plates infected with AdFasL demonstrated a clear nucleosomal pattern of DNA degradation indicative of apoptosis (Fig. 1,
lanes 2 and 3). Thus FasL induces
apoptosis in neonatal cardiac myocytes.
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FasL induces apoptosis in adult cardiac myocytes in vivo.
To extend the above results to adult cardiac myocytes in the intact
animal, AdFasL or Ad-gal was injected into the myocardium of beating
rat hearts, and FasL protein expression and TUNEL was assessed 48 h later. With the use of two different antibodies specific for murine
FasL (encoded by the adenovirus), AdFasL-injected rat hearts exhibited
immunostaining for mouse FasL in cardiac myocytes near the injection
site (Fig. 2A, b and
d). Mouse FasL staining was
not detected in Ad-gal-injected rat hearts (Fig. 2A,
a and c). These control hearts were also negative
for TUNEL staining (Fig. 2B, a). In contrast,
hearts injected with AdFasL exhibited strong TUNEL staining, most of
which was localized to the area surrounding the injection track and
which included myocytes and nonmyocytes (Fig. 2B,
b). Of the 15 hearts injected with AdFasL, 11 contained
TUNEL-positive myocytes (Fig. 2C). In contrast, none of the
15 hearts injected with Ad-gal contained TUNEL-positive cells.
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FasL-induced cardiac myocyte apoptosis requires Fas.
To determine whether FasL-induced cardiac myocyte apoptosis is
a specific event, we tested whether it is receptor dependent. To
accomplish this, we assessed whether intramyocardial injection of
AdFasL would induce apoptosis in the hearts of lpr
mice, a naturally occurring mutant deficient in Fas due to an insertion of an early transposable element that results in premature mRNA termination (1). Because lpr mice develop
lymphoproliferative disease in later life (46, 54), they
were used in the current studies before developing any detectable
abnormalities. Wild-type mice of the same genetic background (MRL/MpJ)
were studied in parallel. Injection with AdFasL induced cardiac myocyte
apoptosis in 3 of 3 wild-type mice (Table
1). In contrast, TUNEL-positive cells
were absent in 2 of 2 AdFasL-injected lpr mice, although the
injections were successful as evidenced by positive -galactosidase staining resulting from the coinjected Ad-gal. This experiment demonstrates that induction of myocyte apoptosis by FasL is a specific event that requires Fas. Taken together, these rat and mouse
studies demonstrate that activation of Fas can result in apoptosis in adult cardiac myocytes in vivo.
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Fas pathway is critical for cardiac myocyte apoptosis and
infarct development due to ischemia-reperfusion.
To test the importance of the Fas pathway for myocyte death and
infarction during ischemia-reperfusion injury in vivo,
wild-type (MRL/MpJ) and lpr mice were subjected to sham
operation or left anterior descending coronary artery occlusion for 30 min, followed by 24 h of reperfusion. At the conclusion of
reperfusion, the sizes of the region at risk and infarct were
quantitated using Evans blue and 2,3,5-triphenyltetrazolium chloride
staining, respectively, as previously described (24).
Figure 3A depicts
representative stained sections from wild-type (a) and
lpr (b) hearts following ischemia-reperfusion in vivo. Despite similar regions at risk (denoted by the absence of blue), the lpr heart has a
markedly smaller infarct (denoted by white) than the wild-type heart.
These parameters were quantitated for 9 wild-type and 8 lpr
animals in Fig. 3B. The region at risk was similar between
genotypes (wild-type, 51.8 ± 4.4%; lpr, 52.3 ± 3.1%; P is not significant). Within these similar regions
at risk, however, the mean infarct size was 62.3% smaller in the
lpr mice compared with wild-type mice (wild-type, 62.9 ± 5.1%; lpr, 23.7 ± 5.4%; P < 0.01). As shown in Fig. 3C, this reduction in infarct size
was accompanied by a 63.8% reduction in myocyte apoptosis in a
parallel cohort of mice (wild-type, 3.62 ± 1.25%;
lpr, 1.31 ± 0.5%; P < 0.01). These
data indicate that the Fas pathway plays a critical role in myocyte
death and the development of MI during ischemia-reperfusion in
vivo.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The significance of the death receptor pathway in cardiac myocyte
apoptosis has been in question. This is appropriate, because "death ligands" do not uniformly activate death pathways in all cell types. For example, tumor necrosis factor (TNF)-
is inefficient at killing many cell types because of its simultaneous activation of
survival pathways (4, 53). In fact, although TNF- can kill cardiac myocytes under some conditions (29, 48), its net effect in the heart during ischemia-reperfusion is
prosurvival as illustrated by increased infarcts in TNFR1 and TNFR2
double knockout mice (30). Our results show that
activation of the Fas pathway can induce apoptosis in neonatal
and adult cardiac myocytes. Moreover, the marked reduction in infarct
size and abundance of apoptotic cardiac myocytes in mice lacking
Fas demonstrates the importance of this pathway in
ischemia-reperfusion injury in vivo.
Fas activation can kill cardiac myocytes. Although Fas signaling has been suggested to modulate cardiac hypertrophy (3, 38) and calcium signaling (13), the ability of this pathway to kill cardiac myocytes efficiently has not been shown. This study demonstrates directly that activation of Fas can induce apoptosis in both cultured neonatal cardiac myocytes and adult cardiac myocytes in vivo. Moreover, this killing is specific as evidenced by the inability of AdFasL to induce apoptosis in the hearts of lpr mice. Although these data establish that the Fas death pathway is functional in cardiac myocytes, it is not known whether Fas activation brings about apoptosis in this cell type primarily via the direct activation of downstream caspases by caspase-8, through activation of the mitochondrial death pathway, or both.
Our results are in agreement with previous indirect data showing that the survival of fetal mouse cardiac myocytes decreases when they are cocultured with FasL-expressing lymphocytes (47). It is interesting to consider why only low levels of cardiac myocyte apoptosis have been observed in response to soluble FasL in some previous studies (17, 55-57). We speculate that this may be the result of inadequate levels and/or presentation of the ligand. Perhaps the high-level expression of FasL from closely neighboring cells achieved with a recombinant adenovirus facilitated killing in our studies.Critical role of the Fas death pathway in ischemia-reperfusion in vivo. Strong proof for the importance of the Fas death pathway in vivo is provided by the 62.3% reduction in infarct size during ischemia-reperfusion in lpr mice. This reduction in overall infarct size was accompanied by a 63.8% decrease in apoptotic cardiac myocytes. A previous study using isolated, perfused preparations showed a 56% reduction in apoptotic myocytes in lpr hearts compared with wild-type hearts (23). Our study extends these ex vivo experiments to the in vivo setting. In addition, we demonstrate for the first time that the decrease in cardiac myocyte apoptosis translates into an actual reduction in infarct size. The similarity between the magnitude of the reductions in myocyte apoptosis in the ex vivo study (performed in the absence of blood) and our in vivo study suggests that Fas deficiency in heart cells, rather than blood cells, is responsible for the reduced death. Although not yet formally proven, the deficiency of Fas on cardiac myocytes themselves is the most likely mechanism.
The quantitatively similar decreases in infarct size and cardiac myocyte apoptosis in our study demonstrate that total and apoptotic cell death were reduced in parallel but do not necessarily indicate that the reduction in cell death resulted solely from less apoptosis. To determine this, one would need to know 1) the proportions of total cell death attributable to necrosis versus apoptosis in this model and 2) the abundance of necrotic cells in lpr versus wild-type mice following ischemia-reperfusion. Because necrosis was not assessed directly in this study, it remains to be determined whether disruption of Fas signaling in the myocardium decreases necrosis as well as apoptosis. There is a precedent for this possibility in T lymphocytes, however, where Fas has been implicated in the regulation of both forms of cell death (20). Whereas ablation of Fas signaling strikingly reduces infarct size during ischemia-reperfusion in vivo, it is noteworthy that it does not result in a complete rescue. The most likely explanations for this are direct activation of the mitochondrial pathway and possibly activation of the death receptor pathway through death receptors other than Fas.Modulating factors.
Whereas the experiments in this study provide strong genetic evidence
for activation of the Fas death pathway during
ischemia-reperfusion, they do not identify the actual
triggering events. The most likely initiating event would be an
increase in the abundance of FasL. Although we were unable to document
this in our in vivo model, upregulation of FasL could be demonstrated
in the concentrated coronary effluents from isolated, perfused hearts
subjected to ischemia-reperfusion (23). A second
potential trigger could be increases in Fas. There is precedent for Fas
being limiting in the activation of the death receptor pathway during
the pathogenesis of autoimmune thyroiditis (15) and
diabetes (10). In fact, there are
significant increases in Fas protein during
ischemia-reperfusion (49, 59). A third
potential regulatory mechanism involves two proteins that
modulate Fas signaling by inhibiting caspase-8: Fas-associated death
domain protein-like-interleukin-1 -converting enzyme inhibitory
protein (FLIP) (22) functions as a dominant negative
inhibitor of procaspase-8, whereas apoptosis repressor with a
caspase recruitment domain (ARC) (28) binds to caspase-8 and inhibits its activity. Of note, during
ischemia-reperfusion, levels of FLIP (43) and ARC
(12, 39) decrease dramatically, which could potentially
contribute to activation of the Fas pathway.
Fas: to grow or die?
Recently, it has become clear that Fas signaling plays a role in
cellular growth as well as death. In T cell receptor-stimulated lymphocyte proliferation, this growth response requires FADD and appears to involve activation of extracellular signal-regulated kinase
and nuclear factor-
B pathways by FLIP (31, 52). The Fas
pathway has also been implicated in cardiac hypertrophy. Transgenic mice with cardiac-specific overexpression of FasL have been found to
exhibit mild cardiac hypertrophy (38). Conversely, mice
that lack Fas (lpr) fail to undergo hypertrophy in response
to pressure overload, although surprisingly FasL appears to be
dispensable (3). FasL-induced hypertrophy in cultured
cardiac myocytes requires phosphorylation and inactivation of glycogen
synthase kinase 3, which occurs in a phosphatidylinositol-3
(PI-3)-kinase-dependent manner. The molecular link between activation
of Fas and PI-3-kinase is presently unclear as are the mechanisms that
determine whether Fas activation will result in hypertrophy or death.
On the basis of cell culture studies (3, 56), it has been
previously suggested that the decision to undergo hypertrophy or death
is regulated in part by the concentration of FasL in the extracellular
space (3). In keeping with this notion, it is likely that
significantly higher FasL levels would be achieved with injections of
AdFasL into the myocardium in the present study where apoptosis
was observed than through transgenesis where it was absent
(38). Given the complexities of pathways unveiled thus
far, however, there are likely to be multiple mechanisms downstream of
Fas that regulate the differential effects of activating this receptor
in a cardiac myocyte.
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ACKNOWLEDGEMENTS |
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We thank Dr. Shani Bialik for insightful discussions and Dr. Daniel Michael for critical comments.
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FOOTNOTES |
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This study was funded by National Heart, Lung, and Blood Institute Grants RO1 HL-60665 and RO1 HL-61550 (to R. N. Kitsis). R. N. Kitsis is the Charles and Tamara Krasne Faculty Scholar in Cardiovascular Research of the Albert Einstein College of Medicine and the recipient of the Monique Weill-Caulier Career Scientist Award.
Address for reprint requests and other correspondence: R. N. Kitsis, Depts. of Medicine (Molecular Cardiology) and Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461 (E-mail: kitsis{at}aecom.yu.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.
First published October 31, 2002;10.1152/ajpheart.00777.2002
Received 5 September 2002; accepted in final form 24 October 2002.
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RESULTS
DISCUSSION
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