© 1997 American Heart Association, Inc.
Articles |
Dilated Cardiomyopathy in Transgenic Mice With Cardiac-Specific Overexpression of Tumor Necrosis Factor-
From the Cardiovascular Research Laboratories, the Division of Cardiology (T.K., C.F.M., C.S.F, B.H.L., A.M.F.) and the Division of Transplant Pathology (A.J.D.), University of Pittsburgh Medical Center, and the Biomedical Engineering Program and Pittsburgh NMR Center for Biomedical Research (S.E.S., A.P.K.), Carnegie Mellon University, Pittsburgh, Pa.
Correspondence to Arthur M. Feldman, MD, PhD, Division of Cardiology, University of Pittsburgh Medical Center, 200 Lothrop St, S 572 Scaife Hall, Pittsburgh, PA 15213. E-mail feldma{at}card2.cath.upmc.edu
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Abstract The failing human heart expresses tumor necrosis factor-
(TNF-). However, its
pathophysiological significance is not clear. We
previously reported that robust overexpression of TNF- in the murine
heart causes lethal myocarditis. In this study, we modified the
transgene to reduce the production of TNF- by preserving the
destabilizing sequence in TNF- cDNA. Expression was driven by the
murine -myosin heavy chain promoter. Use of this modified construct
allowed us to establish a murine transgenic line (TG). TG offspring
were examined at 6, 12, and 24 weeks. All showed a significantly higher
heart weight–to–body weight ratio. Northern blot analysis
confirmed the expression of transgene in the heart, and enzyme-linked
immunosorbent assay demonstrated the presence of TNF- protein. The
TG heart demonstrated a mild, diffuse, lymphohistiocytic
interstitial inflammatory infiltrate. Cardiomyocyte
necrosis and apoptosis were present but not abundant.
Magnetic resonance imaging showed that the TG heart was significantly
dilated with reduced ejection fraction. Although the left
ventricular dP/dtmax was not different at
baseline, its responsiveness to isoproterenol was significantly blunted
in TG. Atrial natriuretic factor was expressed in the TG
ventricle. A group of TG died spontaneously, and subsequent autopsies
revealed exceptional dilatation of the heart, increased lung weight,
and pleural effusion, suggesting that they died of congestive heart
failure. The cumulative mortality rate at 6 months was 23%. In
conclusion, the mouse overexpressing TNF- recapitulated the
phenotype of congestive heart failure. This provides a novel
model to elucidate the role of this cytokine in the development
of congestive heart failure.
Key Words: tumor necrosis factor- • heart failure • transgenic mouse
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Introduction |
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Tumor necrosis factor-
is a proinflammatory cytokine with
pleiotropic biological effects.1 2 Elevated circulating
levels of TNF- have been reported in patients with end-stage
congestive heart failure,3 4 5 6 7 8 9 10 and recent studies suggest a
relationship between the serum levels of TNF- and the severity of
the disease.7 8 9 10 Previously, it was suggested that
inflammatory cells within the cardiac interstitium or in the
circulation were responsible for local cardiac expression and release
of TNF-. However, recent studies report that the
cardiomyocytes are also an abundant source of TNF-
production.11 12 Indeed, failing human
myocardium, but not nonfailing human hearts, express
abundant quantities of TNF-.13 14 15 16 Furthermore, myocytes
have TNF- receptors on their surfaces,17 and these
receptors appear to be released into the circulation during heart
failure.7 13 Several studies in vitro have demonstrated
that TNF- exposure causes a substantial decrease in cardiac
contractility18 19 20 21 and can recapitulate
many of the phenotypic changes associated with the failing heart,
including (1) upregulation of
Gi,22 23 (2) a delay in the
Ca2+ transient,19 24 and (3) induction of
inducible nitric oxide synthase.14 16 21 However, it is
unclear whether cardiac expression of TNF- is important for the
development of the heart failure phenotype or whether it simply
represents an epiphenomenon associated with end-stage
congestive failure.
Recently, we reported that robust cardiac-specific overexpression
of TNF- in transgenic mice was lethal.25 The transgene
construct used in those experiments used the murine -MHC promoter
fused to the coding sequence for murine TNF- to achieve
cardiac-specific overexpression of TNF-. However, to ensure robust
expression, we had deleted the AU-rich destabilizing sequence in the 3'
untranslated region of the TNF- gene.26 27 When that
construct was used, no transgenic mice survived past 11 days of age,
and their hearts demonstrated a florid interstitial
infiltrate with edema. However, we hypothesized that a more modest
overexpression of TNF- might abrogate the lethality associated with
robust expression and thus improve survival and provide a mouse model
of congestive heart failure. Therefore, we modified the transgene to
reduce the extent of TNF- overproduction by including the
AU-rich destabilizing sequence. This modification of the transgene
construct resulted in improved survival and the development of progeny
that display the heart failure phenotype.
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Materials and Methods |
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Construction of the Transgene
A transgene construct was made containing the murine
-MHC
promoter with cDNA to murine TNF-. To generate the plasmid vector,
we first used a PCR-based approach to amplify a portion of the
pGL2-Basic plasmid (Promega), which has a multiple cloning site, a
firefly luciferase gene, and the SV40 T antigen intron and
polyadenylation signals (SVpA). Amplification primers 5'-ggg aag ctt
gat ctt tgt gaa gga acc-3' (nucleotides 1892 to 1909, sense
strand) and 5'-ctt tat gtt ttt ggc gtc ttc ca-3' (complement to
nucleotides 77 to 99) were used to amplify a region of
pGL2-Basic that excluded the luciferase coding sequences and introduced
a HindIII site at the 3' end of the amplified DNA. After
HindIII digestion, the amplified plasmid was self-ligated to
generate a pGL-SVpA vector. Finally, a 5.5-kb Sac
I–Sal I fragment of the murine -MHC promoter (generously
provided by Dr Jeffrey Robins, University of Cincinnati
[Ohio])28 29 was isolated and ligated into
Sac I–Xho I–digested pGL-SVpA to generate
pGL-MHC-SVpA.
RAW 264.7 cells treated with lipopolysaccharide for 6
hours30 were used to generate cDNA to murine TNF-. The
cDNA was amplified with a sense primer (5'-gga gaa cag aaa ctc cag aac
atc c-3') corresponding to TNF- cDNA nucleotides 34 to
5831 and an antisense primer (5'-ggg gat ccc caa gcg atc
ttt att tct ctc-3') containing a BamHI site not found in the
murine sequence, followed by nucleotides complementary to
TNF- cDNA bases 1608 to 1627.31 TNF- cDNA was cloned
then into the pCR 2.1 vector using a TA Cloning Kit (Invitrogen) to
create plasmid pCR-TNF. The identity of the TNF- coding
sequence31 32 was confirmed by sequence analysis
(Sequenase Version 2.0 DNA Sequence Kit, USB). The pCR-TNF was digested
first at the vector EcoRV site. Then HindIII
linkers were added, and the pCR-TNF was digested with
HindIII to create a clonable end. BamHI was added
subsequently to cleave at the BamHI site introduced in the
initial PCR amplification immediately after TNF- cDNA base 1627. The
1624-bp fragment (containing 7 nt of the HindIII linker, 18
bp of the pCR 2.1 vector, TNF- cDNA nucleotides 34 to
1627, and 5 nt from the PCR-introduced BamHI site) of
pCR-TNF was cloned into an 8.4-kb fragment of pGL-MHC-SVpA after a
HindIII/partial BamHI digestion. This digestion
removed SVpA from pGL-MHC-SVpA. BamHI digestion of
pGL-MHC-TNF produced a linear 7.1-kb fragment (MHC-TNF) used for
microinjection into mouse embryos.
Generation and Identification of Transgenic Mice
FVB mice were used for the generation of transgenic animals.
Microinjection of the transgene was accomplished in the Transgenic
Mouse Facility, Children's Hospital of Pittsburgh (Pa) by Dr Maria T.
Sáenz Robles and Suzanne Bertera. After offspring were born, the
tails were biopsied at the age of 10 days. Genomic DNA was isolated
using a proteinase K method previously described.33
Transgenic mice were identified by PCR with a sense primer (5'-cca cat
tct tca gga ttc tct-3') specific to the -MHC promoter exon
228 and an antisense primer (5'-cag cct tgt ccc ttg aag
aga-3') specific to the TNF- cDNA nucleotides 579 to
599,31 as described previously.25
Southern Blot Analysis
The integrity and copy number of the inserted transgene was
examined by Southern blot analysis. After complete digestion by
BamHI, genomic DNA (10 µg/lane) was
electrophoretically separated in a 0.5% agarose gel and transferred
onto a nylon membrane (Zeta-Probe GT, Bio-Rad Laboratories). A 1.1-kb
EcoRI fragment of the transgene, a part of mouse TNF-
cDNA, was used as a hybridization probe. The probe was radiolabeled to
at least 1x108 cpm/µg using a Random Primed DNA Labeling
Kit (Boehringer-Mannheim). After prehybridization with 7% SDS,
500 mmol/L NaP, 1 mmol/L EDTA, 1% bovine serum
albumin, and 100 µg/mL sheared salmon sperm DNA, the
membrane was hybridized with the probe overnight at 65°C and washed
two times with 5% SDS, 40 mmol/L NaP, and 1
mmol/L EDTA at 65°C and three times with 1% SDS, 40
mmol/L NaP, and 1 mmol/L EDTA at 65°C. Radioactive
images from hybridizations were obtained with a PhosphorImager
(Molecular Dynamics) and quantified with ImageQuant software (Molecular
Dynamics). The expected size of the inserted transgene after
BamHI digestion was 7.1 kb. The copy number was calculated
as the ratio of the transgene to the endogenous TNF-
(two copies in each animal).
Pathological Analysis
Mice were euthanized under methoxyflurane anesthesia
before pathological evaluation. All surgical procedures were performed
according to the protocols approved by the Institutional Animal Care
and Use Committee, University of Pittsburgh (Pa). After measurement of
body weight, the heart was excised and rinsed in ice-cold 30
mmol/L KCl. Tissues were either snap-frozen in liquid nitrogen
for RNA and protein analysis or immediately immersion-fixed in
10% neutral buffered formalin for staining with either hematoxylin and
eosin or Masson's trichrome. Apoptotic cells were assessed
using a commercially available TUNEL kit (ApopTag,
Oncor).34
Northern Blot Analysis
Total RNA was extracted from frozen tissues by using an acid
guanidinium thiocyanate–phenol–chloroform method.35 The
concentration of RNA in each sample was assessed
spectrophotometrically. RNA (5 to 10 µg) was electrophoresed in
formaldehyde-agarose gels and transferred to nitrocellulose (Optitran,
Schleicher & Schuell). Hybridization probes were prepared from the
following sources: (1) mouse TNF- cDNA, a 1.1-kb EcoRI
fragment of the transgene, (2) rat atrial natriuretic
factor cDNA,36 and (3) a 24-mer
oligonucleotide complementary to rat 18S ribosomal
RNA.37 cDNA probes were radiolabeled to at least
1x108 cpm/µg using a Random Primed DNA Labeling Kit
(Boehringer-Mannheim). Radiolabeled cDNA probes were hybridized
overnight at 42°C in 50% formamide, 10% dextran sulfate, 5x SSC,
25 mmol/L sodium phosphate, 5x Denhardt's, and 0.2% SDS.
The membranes received a final wash in 0.2x SSC/0.1% SDS at 60°C.
Radioactive images from hybridizations were obtained with a
PhosphorImager (Molecular Dynamics) and quantified with ImageQuant
software (Molecular Dynamics). Then, the membranes were stripped and
rehybridized with the 18S oligonucleotide. The 18S rRNA
oligomer probe (labeled using T4 polynucleotide kinase) was
combined with a 400-fold mass excess of unlabeled 18S
oligonucleotide and hybridized overnight at 50°C in
6x SSC, 0.1% SDS, 0.05% sodium pyrophosphate, and 1x Denhardt's
solution; the membranes were washed at room temperature in 3x
SSC/0.1% SDS. Then, the membranes were reexposed and quantified, and
the results of the cDNA hybridization were normalized to that of the
18S probe to correct for differences in RNA mass and efficiency of
transfer.
RT-PCR
First-strand cDNA was synthesized by reverse transcription of 1
µg of total RNA by using oligo-dT primers according to
manufacturer's instructions (SuperScript II, GIBCO-BRL). Primers
specific to the -MHC promoter exon 128 (5'-tca gag att
tct cca acc cag-3') and complementary to the TNF- cDNA 579 to
59931 (5'-cag cct tgt ccc ttg aag aga-3') were used to
detect the transgene transcripts as described
previously.25
ELISA
Tissue levels of TNF- protein were assessed using a
commercially available ELISA kit for mouse TNF- (Factor-Test-X,
Genzyme) as reported previously.13 25 38 Frozen tissues (5
to 20 mg) were homogenized in 300 to 500 µL ice-cold
phosphate-buffered saline containing 1 mmol/L
phenylmethylsulfonyl fluoride protease inhibitor
(Sigma Chemical Co). After brief centrifugation,
samples were kept on ice for the duration of the assay. Total protein
levels were quantified using a commercially available assay (Bio-Rad
Protein Assay, Bio-Rad Laboratories) with bovine serum albumin
(Sigma) as a standard (0 to 2 mg/mL). Tissue samples were
standardized to 20 µg total protein in 100 µL diluent buffer for
each immunoassay. Mouse TNF- provided by the manufacturer was used
as a standard (0 to 2240 pg/mL). All assays were done in
duplicate. Results were analyzed spectrophotometrically at a
wavelength of 450 nm with a microtiter plate reader. TNF- values are
reported as pg/mL of standardized sample (equivalent to
pg/200 µg total protein).
MRI
Female transgenic mice and wild-type control mice at the ages of
9 and 24 weeks were studied. Images were acquired on a Bruker Avance 7T
spectrometer using a home-built single-loop radiofrequency coil. To
anesthetize the mice, sodium pentobarbital was applied
intraperitoneally in two doses: the first dose was
0.06 mg/g body wt, and 20 minutes later, a second dose of 0.04
mg/g body wt was applied. After sedation, the mouse was placed
prone on the coil, with the heart positioned above the coil center.
Image acquisition was gated to both the respiratory and cardiac cycles.
A pilot coronal image was obtained from which the long axis of the
heart was identified. Eight oblique transverse slices, with a slice
thickness of 1 mm and an interslice gap of 0.2 mm, provided
short-axis images through the heart, covering the entire left
ventricle. The short-axis images were acquired with a spin echo imaging
sequence with the following parameters: echo time, 11.3
milliseconds; field of view, 1.5 cm; matrix size, 128x128; number of
averages, 4; and repetition time, 
1 second. The acquisition order of
the multislice set was rotated so that every slice was obtained at
eight different time points (24 milliseconds apart), allowing for
images to be obtained from end diastole, through systole,
and into mid diastole (the average cardiac cycle was 275
milliseconds). Diffusion gradients were used to crush the signal from
flowing blood. The left ventricular volume was estimated by
tracing the intraventricular area in several
consecutive short-axis images where each slice was 1.2 mm thick.
The first image acquired after the R wave was chosen as end
diastole. End systole was taken as the image when the left
ventricular opening was minimal. In several animals, the
heart was weighed after the study and compared with the MRI-estimated
ventricular mass, where the specific gravity of
myocardium was 1.055 g/cm3.
Left Ventricular Pressure Measurement
Five 12-week-old and seven 24-week-old transgenic mice and five
12-week-old and five 24-week-old wild-type control mice were studied.
All mice were female, except for three transgenic and two wild-type
mice at 12 weeks of age. After anesthetization with 2.5% Avertin (18
µL/g body wt IP, Aldrich Chemical Co), mice were placed in a supine
position and surgically intubated with a modified 20-gauge needle
connected to a volume-cycled rodent ventilator (Harvard
Apparatus) with a tidal volume of 0.2 to 0.4 mL and
respiratory rate of 110/min. The chest was opened, and a 1.4F
micromanometer catheter (Millar Instruments) was
inserted into the left ventricle through the apex. Left
ventricular pressure was recorded at the baseline and 2
minutes after low and high doses of isoproterenol injection (0.1 and 1
µg IP). All data were digitized at 1 kHz and stored on a customized
personal computer for subsequent analysis.
Statistical Analysis
All statistical analysis was performed using SPSS
software (SPSS Inc). The results are presented as mean±SD,
unless mentioned otherwise. Student's t test was used to
compare each variable between the transgenic mice and the
age-matched control mice. A Mann-Whitney rank-sum test was used to
compare the mice that had died spontaneously with the mice that were
intentionally killed for study, because those that died spontaneously
had a significantly larger variance as a group. ANOVA, with or without
repeated measures, was used when more than two groups were compared.
The post hoc multiple comparisons were made by the Student-Newman-Keuls
test. Mortality rate was estimated by Kaplan-Meier survival
analysis. Differences were considered significant at a value of
P<.05.
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Generation of Transgenic Mice
The transgene construct was microinjected into the pronuclei of one-cell mouse embryos, after which the embryos were surgically reimplanted into pseudopregnant mice. Screening of the offspring by PCR identified three potential founders harboring the TNF-
transgene,
all of which were grossly indistinguishable from nontransgenic
littermates. The Southern blot analysis of the founders is
shown in Fig 1
. The probe detected both
transgene and endogenous TNF-. The estimated copy number
of transgene in each founder is as follows: founder 1, 39.8±2.6
(mean±SEM); founder 2, 22.3±1.2; and founder 3, 21.0±1.3. One mouse
(founder 1) was male but produced no offspring despite mating with
several females and was killed at the age of 39 weeks to examine the
pathological changes in the heart, which showed a diffuse
lymphohistiocytic inflammatory infiltrate in the interstitium. A second
mouse (founder 2) was female and delivered 79 offspring in six litters.
However, only one of them, which died at 3 days of age, carried the
transgene. This founder died spontaneously at 44 weeks of age, and a
subsequent autopsy demonstrated pathology consistent with heart
failure, including ventricular dilatation and
pulmonary edema. The third mouse (founder 3) was also female
and produced a number of offspring harboring the TNF- transgene.
This founder also developed subsequent congestive heart failure at 50
weeks of age and died with a profoundly dilated heart. The TNF-
transgene appeared to be X-linked, since only female mice harbored the
transgene when transgenic males were outcrossed with wild-type females.
Furthermore, when transgenic females were outcrossed with wild-type
males, both males and females harbored the transgene.
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After the screening at 10 days, 15 of 176 transgenic mice were found to
have died spontaneously. This was in marked contrast to an absence of
death in wild-type littermates (n=195). As seen in Fig 2, the survival rate for the transgenic
mice was substantially different from that of littermate control mice,
with the mean time to death being 297±17 (mean±SEM) days
(P<.005). The cumulative mortality rate at 6 months was
23%. Although there were no statistical differences in mortality
between transgenic males and females, the generations of mice had
significant effects on mean survival time (F0, 351 days; F1, 209±25
days; F2, 160±2 days; and F3, 86±2 days; P<.05).
Subsequent autopsies suggested that at least 11 of the 15 deaths were
associated with congestive heart failure.
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Expression of TNF- Transgene and Protein in the Heart
A group of transgenic mice and wild-type control mice was killed
for analysis at the ages of 6, 12, and 24 weeks. Transgene
expression was assessed using Northern blot analysis of total
RNA from various tissues, including heart, lung, and liver. Robust
expression of the transgene was found in the heart; however, no
transgene expression was noted in either the liver or the lung (Fig 3). RT-PCR detected multiple bands for
the TNF- transgene, consistent with our earlier observation
of the presence of multiple splice variations of the TNF-
transgene.25 Fig 4 shows
cardiac TNF- levels by ELISA in transgenic mice and wild-type
control mice at each age. TNF- levels were significantly higher in
the transgenic mice than in littermate control mice
(P<.001). However, age did not appear to influence TNF-
levels, since there was virtually no difference in levels at 6, 12, and
24 weeks. Similarly, gender had no effects on TNF- levels:
12-week-old males (269±70 pg/mL, n=3) and females (361±138
pg/mL, n=6) had similar levels of TNF-. In addition, TNF-
levels in mice that died spontaneously (243±94 pg/mL) were
similar to those in the transgenic mice that were killed for study.
However, we cannot exclude the possibility that proteolysis decreased
the levels of TNF- in the carcasses. Cardiac levels of TNF- in
transgenic mice of the present study were approximately an order of
magnitude less than those found in the heart of a mouse expressing the
TNF- transgene in which the 3' destabilizing region had been deleted
(1483 pg/mL).25 Immunoreactive TNF- levels in
either lung, liver, or sera were not different between 12-week-old
transgenic mice and wild-type control mice (Table 1), consistent with the Northern
blot analysis demonstrating that the transgene transcripts were
limited to the heart.
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Gross Pathology and Histology
Gross pathological observation of the hearts harboring the
transgene suggested the presence of cardiac enlargement. This finding
was confirmed by the presence of an elevation in heart weight–to–body
weight ratios as early as 6 weeks of age (Table 2). An elevation in heart weight was also
recognized in these animals.
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The histology of the transgenic animals was easily distinguishable from
age-matched control animals at all ages (6, 12, and 24 weeks), and an
evolution of histopathological changes developed over time.
Representative images are presented in Fig 5. Changes in the interstitium were
obvious by routine light microscopy. There was an increase and
hypertrophy of interstitial cells, which
appeared to consist mostly of histiocytes, fewer lymphocytes,
and hypertrophied interstitial connective tissue cells.
Apoptotic cell death in this population was evident both by
routine light microscopy and by the TUNEL assay. There was also mild
interstitial edema, an apparent increase in the
production of matrix material, and focal
interstitial fibrosis. The fibrosis in some animals was
more pronounced near the endocardium. The interstitial
changes were associated with mild myocyte hypertrophy and
focal myocyte degeneration in the form of rare areas of single-cell
dropout and occasional myocyte multinucleation. Apoptotic
myocytes were present but seen rarely.
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Autopsies were also performed with 16 transgenic mice, including two
founders, which died spontaneously during the study period. Both
ventricles and atria were enlarged extremely in these animals, and lung
weight was increased also (Table 2
). Pleural effusions with or without
ascites were present in nine mice, and organized thrombi were
observed in six of 16 atria. Exceptional dilatation of the heart
accompanied by increased lung weight and pleural effusion suggested
that most of these animals (at least 12 of 16) died because of
congestive heart failure.
The histopathological changes in the interstitium were similar qualitatively to those seen in the transgenic mice that were killed for study, but in several of the mice, there was a noticeable increase in the lymphocytic component of the interstitial cells. This was associated with more clearly recognizable myocyte injury, myocyte and interstitial cell multinucleation, and rare but definite myocyte apoptosis. The interstitial fibrosis was relatively severe in some of the animals, but overall, interstitial fibrosis was not an overriding feature. The endocardium and pericardium were slightly fibrotic, but there was no evidence of significant pathological change in the intramyocardial branches of the coronary arteries.
Cardiac Function
Because of the small size and rapid heart rate of the
transgenic mouse heart, functional analysis of transgenic
myocardium has been challenging. In particular, sensitive
measures of in vivo cardiac function have been technically difficult.
However, recent advances in MRI technology have provided the capability
to evaluate cardiac mass and function in the anesthetized
mouse. To verify the accuracy of MRI volume measurement, we compared
ventricular mass estimated by MR (VMMR) with
that by gravimetry (VMG) in seven transgenic and five
wild-type animals (Fig 6). The
least-squares regression analysis yields the following line:
VMMR=1.02xVMG-3.06 (r=.983,
P<.0001). The errors between the two methods were
0.28±2.70 mg, which indicated the high accuracy and sensitivity of MRI
volume measurement. These results agree with those reported in our
previous study.39 Representative MR images
from a 24-week-old transgenic mouse and an age-matched wild-type
control mouse are shown in Fig 7. The
coronal view image of the transgenic mouse (Fig 7A) clearly
demonstrated that the heart was dilated and globoid. Left
ventricular volume was estimated by tracing the
intraventricular area in five consecutive
short-axis images, where each slice was 1.2 mm thick. The
end-diastolic and end-systolic volumes were 0.104
and 0.052 mL, respectively, in the transgenic mouse (ejection fraction,
50%) and 0.064 and 0.018 mL, respectively, in the wild-type control
mouse (ejection fraction, 72%). Cumulative data, presented in
Table 3, demonstrate a progressive
increase in end-diastolic and end-systolic volumes
with age in mice overexpressing TNF-. As a result, left
ventricular ejection fraction was decreased significantly
at 24 weeks of age (P<.01).
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Left ventricular pressure was measured in 12 transgenic and
10 wild-type mice at 12 or 24 weeks of age. Because neither age nor
gender had a significant effect on hemodynamic
parameters, results are summarized as a whole. There were
no significant differences in heart rate or systolic blood
pressure between the transgenic mice (342±37 bpm, 56±9 mm Hg)
and the wild-type control mice (364±49 bpm, 66±15 mm Hg). After
0.1 and 1 µg isoproterenol injection, heart rate increased in the
transgenic mice as well as in the control mice (113±16% versus
111±15% and 137±20% versus 135±20%). Blood pressure did not
change significantly after isoproterenol injections in either group. We
used left ventricular dP/dtmax as an index of
contractility. As shown in Fig 8, although left ventricular
dP/dtmax was not significantly different at baseline, its
responsiveness to isoproterenol was blunted in the transgenic animals
(P<.05). In 8 mice in which we had performed MRI on the day
preceding the pressure measurement, there was a weak but significant
correlation between the dP/dtmax at baseline and the
ejection fraction estimated by MRI (r=.73,
P<.05).
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Expression of Atrial Natriuretic Factor mRNA
To assess whether the hearts overexpressing TNF-
activated the fetal gene program consistent with heart
failure, we evaluated the levels of mRNA encoding atrial
natriuretic factor in the ventricular
myocardium. As seen in Fig 9, hearts with TNF- overexpression demonstrated reexpression of atrial
natriuretic factor in the ventricle, whereas no atrial
natriuretic factor expression was obvious in hearts from
wild-type littermate control mice.
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Discussion |
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That end-stage congestive heart failure is associated with a marked increase in circulating TNF-
levels has been reported by
numerous investigators.3 4 5 6 7 8 9 10 Furthermore, there appears to
be a direct relationship between disease severity and circulating
levels of TNF-.7 8 9 10 Additionally, recent studies have
demonstrated that although the nonfailing heart does not express
TNF-, the failing myocardium expresses abundant amounts
of this proinflammatory cytokine.13 14 16 Whereas
initial reports suggested that TNF- was expressed by inflammatory
cells within the myocardium, it is now clear that myocytes
themselves can express TNF- at times of stress.11 12
However, the precise role of TNF- in the pathophysiology of
congestive failure and/or the transition from compensated to
decompensated heart failure remains unclear. Similarly, studies have
not defined whether these changes in cardiac TNF- expression are
pathophysiologically important or simply an
epiphenomenon associated with end-stage heart failure.
In the present study, we demonstrate that chronic overexpression of
TNF- results in the development of a dilated
cardiomyopathy that shows (1)
ventricular hypertrophy, (2)
ventricular dilatation, (3) interstitial
infiltrates, (4) interstitial fibrosis, (5) rare myocyte
apoptosis, (6) a diminished ejection fraction, (7) attenuation
of ß1-adrenergic responsiveness, and (8) expression of
atrial natriuretic factor in the ventricle. Additionally,
mice overexpressing the TNF- transgene had a marked increase in
mortality. More than half of the mice that died spontaneously
presented with exceptional dilatation of the heart, increased
lung weight, and pleural effusion, suggesting that they died of
congestive heart failure.
In an earlier report,25 we demonstrated that robust
overexpression of TNF- in a mouse resulted in the development of a
lethal myocarditis before the completion of weaning. By contrast, the
mice in the present report demonstrated levels of TNF- that were
approximately an order of magnitude less than those reported in the
mouse with lethal myocarditis. It is unlikely that this disparity could
be attributed to the analysis of tissue samples, for the
tissues in the earlier study were obtained from carcasses, whereas
those in the present study were obtained from fresh specimens.
Myocardial TNF- levels from the carcasses of mice that died
spontaneously in the present study were similar to those in the
animals that were randomly killed for study. Rather, it would appear
that the destabilizing region in the 3' tail of the TNF- gene plays
an important part in regulating TNF- expression.
Although only a single transgenic line was established in the
present study, three potential founders were produced, and two of
them (founders 2 and 3) died of congestive heart failure. The gross
pathology and histology were indistinguishable between these two
animals. Furthermore, the third potential founder (founder 1), which
was killed before the development of heart failure, also demonstrated
mild diffuse myocarditis with a lymphohistiocytic infiltrate.
Additionally, at least two potential founders harboring the more robust
construct developed a similar though lethal
phenotype.25 Thus, five founders overexpressing
TNF- constructs demonstrated similar cardiac phenotypes.
Therefore, it is unlikely that identical insertion sites could have
been a causative factor for the development of myocarditis and
congestive heart failure in these animals.
Transgenic progeny demonstrated phenotypic
heterogeneity, since survival was considerably
different among different mice and since TNF- levels did not appear
to reflect prognosis. However, this finding was not surprising, since
clinical heterogeneity is a hallmark in patients with
heart failure as well as in patients with genetically linked heart
muscle disease.40 41 It has been proposed that
hypertrophy, myocyte loss, and interstitial
fibrosis are early components of the transition from compensated to
decompensated myocardium.42 Indeed, the
development of cardiac dilatation in the transgenic mouse occurs over a
period of 6 months, and hypertrophy and fibrosis appear to
precede dilatation and diminished pump function.
It might also be of interest to compare cardiac TNF- protein levels
in our transgenic mice with those reported in human heart failure.
There are two reports that used ELISA to demonstrate the presence of
TNF- protein in the failing human heart: one study13
reported 200 pg/g protein, and the other15 reported
4 pg/mg protein. In contrast, TNF- in our transgenic mice was
300 pg/mL, which is 1500 pg/mg when normalized for the
amount of protein loaded in each well (20 µg/100 µL). There
appears to be more TNF- in our transgenic hearts than in the failing
human heart. However, such comparisons may be problematic,
since the values were obtained by different methods. Furthermore,
nonspecific background activity from tissue homogenates
limits our ability to detect low levels of TNF- by ELISA and may
result in an overestimation of absolute TNF- levels.
The measurement of cardiac mass and function in the mouse is
technically challenging because of the small size of the heart and its
rapid rate. Transthoracic
echocardiography has been used successfully to
evaluate the transgenic mouse heart.43 44 45 46 In the
present study, we have taken advantage of the recent adaptation of
MRI technology to noninvasively assess cardiac structure and function
in the mouse. MRI is able to provide simultaneous measures
of morphology and function by gating the image acquisition to both the
electrocardiogram and the respiratory signal, thereby
abrogating motion artifacts and ensuring that images are obtained at
specific points through the cardiac cycle. Furthermore, multiple image
slices in MRI can be obtained in the same amount of time required for a
single slice. This permits acquisition of eight short-axis slices at
many different points through the cardiac cycle in a decreased amount
of time. A previous study has demonstrated the ability of MRI to detect
relatively small changes in cardiac mass secondary to
catecholamine induced
hypertrophy.39 In the present study, we
demonstrate the usefulness of MRI in evaluating left
ventricular hypertrophy, cavity dilatation, and
function in the TNF- transgenic mice compared with wild-type control
mice.
Although the present study strongly suggests an important
pathophysiological role for TNF- in the
pathogenesis of end-stage heart failure, we cannot exclude the
possibility that other pathways are of complementary importance in the
development of the heart failure phenotype. For example,
chronic overexpression of the ß1-adrenergic
receptor47 as well as overexpression of
Gs48 can effect phenotypic
changes associated with congestive heart failure. Furthermore, this
mouse model does not provide the opportunity to evaluate the mechanisms
that initiate the expression of TNF- after myocardial damage. In
addition, tissue TNF- levels observed in the transgenic mice appear
higher than those reported in the failing human heart. However, the
TNF- transgenic mice develop a primary phenotype that is
consistent with congestive heart failure, displaying both
cardiac dilatation and left ventricular dysfunction.
Therefore, it should provide a novel tool with which to analyze
physiological and biochemical changes that
accompany the transition from compensated to decompensated
myocardium and the development of end-stage heart failure.
Additionally, the opportunity to modify or rescue the heart failure
phenotype by directed crossbreeding with mice harboring
selected gene mutations will facilitate an understanding of the
mechanisms that compensate or progress cardiac dysfunction. Similarly,
the TNF- overexpression model may provide a unique platform for
preclinical evaluation of gene transfer or pharmacological therapy.
|
Selected Abbreviations and Acronyms |
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Acknowledgments |
|---|
Dr Kubota is the recipient of a Japan Heart Foundation & Bayer Yakuhin Research Grant Abroad. The MRI work was supported by National Institutes of Health grant RR-03631 and Research Career Development Award HL-02847 and the National Science Foundation Graduate Research Traineeship Program (BIR-9256343).
Received May 13, 1997; accepted July 25, 1997.
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References |
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G. Hall, I. S. Singh, L. Hester, J. D. Hasday, and T. B. Rogers Inhibitor-{kappa}B kinase-{beta} regulates LPS-induced TNF-{alpha} production in cardiac myocytes through modulation of NF-{kappa}B p65 subunit phosphorylation Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2103 - H2111. [Abstract] [Full Text] [PDF]
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S. Kawano, T. Kubota, Y. Monden, N. Kawamura, H. Tsutsui, A. Takeshita, and K. Sunagawa Blockade of NF-{kappa}B ameliorates myocardial hypertrophy in response to chronic infusion of angiotensin II Cardiovasc Res, September 1, 2005; 67(4): 689 - 698. [Abstract] [Full Text] [PDF]
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M. Satoh, M. Nakamura, T. Akatsu, Y. Shimoda, I. Segawa, and K. Hiramori Myocardial osteopontin expression is associated with collagen fibrillogenesis in human dilated cardiomyopathy Eur J Heart Fail, August 1, 2005; 7(5): 755 - 762. [Abstract] [Full Text] [PDF]
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M. Brown, M. McGuinness, T. Wright, X. Ren, Y. Wang, G. P. Boivin, H. Hahn, A. M. Feldman, and W. K. Jones Cardiac-specific blockade of NF-{kappa}B in cardiac pathophysiology: differences between acute and chronic stimuli in vivo Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H466 - H476. [Abstract] [Full Text] [PDF]
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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]
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M. Li, D. Georgakopoulos, G. Lu, L. Hester, D. A. Kass, J. Hasday, and Y. Wang p38 MAP Kinase Mediates Inflammatory Cytokine Induction in Cardiomyocytes and Extracellular Matrix Remodeling in Heart Circulation, May 17, 2005; 111(19): 2494 - 2502. [Abstract] [Full Text] [PDF]
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T. Ueland, A. Yndestad, E. Oie, G. Florholmen, B. Halvorsen, S. S. Froland, S. Simonsen, G. Christensen, L. Gullestad, and P. Aukrust Dysregulated Osteoprotegerin/RANK Ligand/RANK Axis in Clinical and Experimental Heart Failure Circulation, May 17, 2005; 111(19): 2461 - 2468. [Abstract] [Full Text] [PDF]
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S. D. Prabhu Cytokine-Induced Modulation of Cardiac Function Circ. Res., December 10, 2004; 95(12): 1140 - 1153. [Abstract] [Full Text] [PDF]
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M. Ikeuchi, H. Tsutsui, T. Shiomi, H. Matsusaka, S. Matsushima, J. Wen, T. Kubota, and A. Takeshita Inhibition of TGF-{beta} signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction Cardiovasc Res, December 1, 2004; 64(3): 526 - 535. [Abstract] [Full Text] [PDF]
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M. Sun, F. Dawood, W.-H. Wen, M. Chen, I. Dixon, L. A. Kirshenbaum, and P. P. Liu Excessive Tumor Necrosis Factor Activation After Infarction Contributes to Susceptibility of Myocardial Rupture and Left Ventricular Dysfunction Circulation, November 16, 2004; 110(20): 3221 - 3228. [Abstract] [Full Text] [PDF]
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S. SHARMA, J. V. ADROGUE, L. GOLFMAN, I. URAY, J. LEMM, K. YOUKER, G. P. NOON, O. H FRAZIER, and H. TAEGTMEYER Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart FASEB J, November 1, 2004; 18(14): 1692 - 1700. [Abstract] [Full Text] [PDF]
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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]
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R. von Harsdorf "Fas-ten" Your Seat Belt: Anti-apoptotic Treatment in Heart Failure Takes Off Circ. Res., September 17, 2004; 95(6): 554 - 556. [Full Text] [PDF]
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A. Khoynezhad, Z. Jalali, and A. J. Tortolani Apoptosis: Pathophysiology and therapeutic implications for the cardiac surgeon Ann. Thorac. Surg., September 1, 2004; 78(3): 1109 - 1118. [Abstract] [Full Text] [PDF]
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D. Engel, R. Peshock, R. C. Armstong, N. Sivasubramanian, and D. L. Mann Cardiac myocyte apoptosis provokes adverse cardiac remodeling in transgenic mice with targeted TNF overexpression Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1303 - H1311. [Abstract] [Full Text] [PDF]
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R. Ramani, M. Mathier, P. Wang, G. Gibson, S. Togel, J. Dawson, A. Bauer, S. Alber, S. C. Watkins, C. F. McTiernan, et al. Inhibition of tumor necrosis factor receptor-1-mediated pathways has beneficial effects in a murine model of postischemic remodeling Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1369 - H1377. [Abstract] [Full Text] [PDF]
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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]
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C. Berthonneche, T. Sulpice, F. Boucher, L. Gouraud, J. de Leiris, S. E. O'Connor, J.-M. Herbert, and P. Janiak New insights into the pathological role of TNF-{alpha} in early cardiac dysfunction and subsequent heart failure after infarction in rats Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H340 - H350. [Abstract] [Full Text] [PDF]
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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]
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A. M Janczewski, M. Zahid, B. H Lemster, C. S Frye, G. Gibson, Y. Higuchi, E. G Kranias, A. M Feldman, and C. F McTiernan Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model Cardiovasc Res, June 1, 2004; 62(3): 468 - 480. [Abstract] [Full Text] [PDF]
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Y. Higuchi, C. F. McTiernan, C. B. Frye, B. S. McGowan, T. O. Chan, and A. M. Feldman Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-{alpha}-Induced Cardiomyopathy Circulation, April 20, 2004; 109(15): 1892 - 1897. [Abstract] [Full Text] [PDF]
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D. L. Mann, J. J.V. McMurray, M. Packer, K. Swedberg, J. S. Borer, W. S. Colucci, J. Djian, H. Drexler, A. Feldman, L. Kober, et al. Targeted Anticytokine Therapy in Patients With Chronic Heart Failure: Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL) Circulation, April 6, 2004; 109(13): 1594 - 1602. [Abstract] [Full Text] [PDF]
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M. B. P. Soares, R. S. Lima, L. L. Rocha, C. M. Takyia, L. Pontes-de-Carvalho, A. C. Campos de Carvalho, and R. Ribeiro-dos-Santos Transplanted Bone Marrow Cells Repair Heart Tissue and Reduce Myocarditis in Chronic Chagasic Mice Am. J. Pathol., February 1, 2004; 164(2): 441 - 447. [Abstract] [Full Text] [PDF]
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Q. Wang, H. R. Brunner, and M. Burnier Determination of cardiac contractility in awake unsedated mice with a fluid-filled catheter Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H806 - H814. [Abstract] [Full Text] [PDF]
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A. M. Feldman The emerging role of pharmacogenomics in the treatment of patients with heart failure Ann. Thorac. Surg., December 1, 2003; 76(6): S2246 - 2253. [Full Text] [PDF]
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Z. I. Dibbs, A. Diwan, S. Nemoto, G. DeFreitas, M. Abdellatif, B. A. Carabello, F. G. Spinale, G. Feuerstein, N. Sivasubramanian, and D. L. Mann Targeted Overexpression of Transmembrane Tumor Necrosis Factor Provokes a Concentric Cardiac Hypertrophic Phenotype Circulation, August 26, 2003; 108(8): 1002 - 1008. [Abstract] [Full Text] [PDF]
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M. Flesch, A. Hoper, L. Dell'Italia, K. Evans, R. Bond, R. Peshock, A. Diwan, T. A. Brinsa, C.-C. Wei, N. Sivasubramanian, et al. Activation and Functional Significance of the Renin-Angiotensin System in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor Circulation, August 5, 2003; 108(5): 598 - 604. [Abstract] [Full Text] [PDF]
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X. He, Y. Liu, V. Sharma, R. T. Dirksen, R. Waugh, S.-S. Sheu, and W. Min ASK1 Associates with Troponin T and Induces Troponin T Phosphorylation and Contractile Dysfunction in Cardiomyocytes Am. J. Pathol., July 1, 2003; 163(1): 243 - 251. [Abstract] [Full Text] [PDF]
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E. S. Chung, M. Packer, K. H. Lo, A. A. Fasanmade, and J. T. Willerson Randomized, Double-Blind, Placebo-Controlled, Pilot Trial of Infliximab, a Chimeric Monoclonal Antibody to Tumor Necrosis Factor-{alpha}, in Patients With Moderate-to-Severe Heart Failure: Results of the Anti-TNF Therapy Against Congestive Heart failure (ATTACH) Trial Circulation, July 1, 2003; 107(25): 3133 - 3140. [Abstract] [Full Text] [PDF]
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D. R. Murray and G. L. Freeman Proinflammatory Cytokines: Predictors of a Failing Heart? Circulation, March 25, 2003; 107(11): 1460 - 1462. [Full Text] [PDF]
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H. Oral, N. Sivasubramanian, D. B. Dyke, R. H. Mehta, P. M. Grossman, K. Briesmiester, W. P. Fay, F. D. Pagani, S. F. Bolling, D. L. Mann, et al. Myocardial Proinflammatory Cytokine Expression and Left Ventricular Remodeling in Patients With Chronic Mitral Regurgitation Circulation, February 18, 2003; 107(6): 831 - 837. [Abstract] [Full Text] [PDF]
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B. London, L. C. Baker, J. S. Lee, V. Shusterman, B.-R. Choi, T. Kubota, C. F. McTiernan, A. M. Feldman, and G. Salama Calcium-dependent arrhythmias in transgenic mice with heart failure Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H431 - H441. [Abstract] [Full Text] [PDF]
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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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C. Steenbergen, C. A. Afshari, J. G. Petranka, J. Collins, K. Martin, L. Bennett, A. Haugen, P. Bushel, and E. Murphy Alterations in apoptotic signaling in human idiopathic cardiomyopathic hearts in failure Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H268 - H276. [Abstract] [Full Text] [PDF]
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L. Fernandez-Celemin, N. Pasko, V. Blomart, and J.-P. Thissen Inhibition of muscle insulin-like growth factor I expression by tumor necrosis factor-alpha Am J Physiol Endocrinol Metab, December 1, 2002; 283(6): E1279 - E1290. [Abstract] [Full Text] [PDF]
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H. L. Li, J. Suzuki, E. Bayna, F.-M. Zhang, E. Dalle Molle, A. Clark, R. L. Engler, and W. Y. W. Lew Lipopolysaccharide induces apoptosis in adult rat ventricular myocytes via cardiac AT1 receptors Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H461 - H467. [Abstract] [Full Text] [PDF]
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H. Funakoshi, T. Kubota, Y. Machida, N. Kawamura, A. M. Feldman, H. Tsutsui, H. Shimokawa, and A. Takeshita Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2159 - H2166. [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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