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,§
* Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
Huffington Center on Aging, Houston, Texas 77030, USA;
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA; and
§ Department of Cardiovascular Sciences, Baylor College of Medicine, Houston, Texas 77030, USA
1Correspondence: Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA. E-mail: schwartz{at}bcm.tmc.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: IGF-I • SIS2 transgene • systolic function • hypertension
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Insulin-like growth factor I (IGF-I) is a 70 amino acid peptide hormone
produced primarily by the liver in adults in response to growth hormone
(GH) secretion by the pituitary gland. IGF-I is the actual mediator of
several effects attributed to GH, including increased skeletal muscle
mass and bone growth (1)
. In cultured neonatal ventricular
myocytes, the addition of IGF-I induces DNA synthesis (2)
(3)
and the transcription of several genes associated with
hypertrophy and hyperplasia, including myosin light chain-2, troponin
and 
-skeletal actin (4)
. The addition of IGF-I to adult
cultured cardiomyocytes induces only a hypertrophic response,
characterized by increased myofibril production (5)
.
In vivo, IGF-I and its receptor are up-regulated in
experimentally infarcted ventricles, possibly followed by DNA
replication and mitotic division of a portion of the remaining
cardiomyocytes (6
, 7)
. IGF-I protects against apoptosis in
cultured (8)
and primary cardiomyocytes (9)
and in a mouse model of ischemic injury (10)
. A transgenic
mouse with significantly increased IGF-I serum levels exhibits
cardiomyocyte hyperplasia but no hypertrophy (11)
. IGF-I
and/or GH have been shown to improve cardiac performance in
experimental (12
, 13)
and human patient cardiac failure
(14
, 15)
. Consequently, IGF-I and GH are being seriously
considered as potential therapeutic agents for situations in which
hypertrophy and/or hyperplasia of cardiomyocytes would be desirable,
such as postmyocardial infarction or hypocontracting cardiomyopathies
(16
, 17)
.
In contrast to these beneficial effects, however, IGF-I has been
implicated as a primary factor in the development of cardiac
hypertrophy under conditions of pressure overload (18)
.
IGF-I stimulates collagen production in primary cultures of
mechanically loaded cardiac fibroblasts (19)
and in
hypertensive humans (20)
. Patients with hypersecretion of
GH (acromegaly), and consequently IGF-I, often develop a cardiomyopathy
characterized by interstitial fibrosis, mononuclear infiltration, and
myocyte necrosis (16)
. Systolic dysfunction is a common
late-stage finding in these patients (21)
. Administration
of octreotide, which inhibits GH secretion, can partially relieve these
effects (22)
. Given these conflicting observations, we
considered it imperative to determine whether the long-term effects of
IGF-I on cardiac function were of a physiological or pathological
nature. Here we report that persistent expression of IGF-I in a
transgenic model initially induced an analog of physiologic
hypertrophy, characterized by increased cardiac mass and improved
systolic performance. However, later in life this hypertrophy
progressed to a pathological condition characterized by decreased
systolic performance and increased interstitial fibrosis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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as Sk 733 IGF-I 3'Sk. SIS2 transgenics and control
mice were of the inbred FVB background strain. Control animals were
either littermates lacking the SIS2 transgene or FVB controls purchased
from Charles River Laboratories (Wilmington, Mass.). All animals were
housed at Baylor College of Medicine in accordance with National
Institutes of Health guidelines. Animals were kept on a 10 h
light/14 h darkness schedule and were fed autoclaved chow ad libitum.
IGF-I radioimmunoassay
Rodent and human total IGF-I concentrations in serum and heart
homogenates were determined by species-specific radioimmunoassay
(Diagnostic Systems Labs, Webster, Tex.) (rodent) or IRMA (human).
Serum samples were assayed per manufacturer's instructions. Heart
homogenates were prepared by powdering whole mouse hearts under liquid
N2 suspension in 4°C RIPA buffer
[phosphate-buffered saline (PBS), 1% Nonidet P-40, 0.5% sodium
deoxycholate, 0.1% sodium dodecyl sulfate] plus protease inhibitors
[1 mg/ml Pefabloc (Boehringer Mannheim, Indianapolis, Ind.), 0.5 mg/ml
EDTA, 10 µg/ml pepstatin, 1 µg/ml aprotinin)] and homogenized.
Serum and heart homogenates' human and rodent IGF-I levels were then
assayed per manufacturer's instructions, except that homogenates were
subjected to a single freeze/thaw cycle prior to assay to increase
recovery of the hormone.
Pulsed Doppler measurements of systolic performance
Our method for pulsed Doppler measurements has been described
(24)
.
Immunohistochemistry
Hearts from control and SIS2 mice were excised, blotted dry, and
flash frozen in 2-methyl-butane chilled with liquid
N2. Tissue sections (6 µM) were produced and
mounted on polylysine-coated slides. Slides were fixed at -20°C for
20 min in 50 mM glycine in 70% ethanol adjusted to pH 2.0. A 1:20
dilution of conditioned media from a hybridoma expressing anti-rat
sarcomeric myosin IgG (hybridoma MF20, University of Iowa Developmental
Studies Hybridoma Bank, Iowa City) was applied to the slides for 30
min. Slides were rinsed three times for 5 min with PBS. An
FITC-conjugated sheep anti-mouse IgG secondary antibody (Boehringer
Mannheim) was applied to slides for 30 min. Slides were rinsed three
times for 5 min with PBS. A 200 ng/ml Hoechst 33258 solution was
applied to slides for 5 min to stain nuclei.
Fibrosis quantitation
After paraffin embedding, 4 µM sections were produced and
mounted on polylysine-coated slides. Slides were stained with Sirius
red/picric acid. Overlapping partial images of heart cross sections
were captured at 40x with a microscope-mounted digital camera.
Composite images of complete heart cross sections were assembled and
quantitation of collagen and noncollagen material was performed.
Statistical analysis
Data sets were compared using Student's t test, the
nonparametric sign test, or analysis of variance, as appropriate.
P < 0.05 was considered significant. Results are
reported as mean ± standard error.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-skeletal actin promoter, human IGF-I
cDNA, -skeletal actin 3'UTR) transgene had been partially
characterized in a previous study (23)
, which showed
transgenic mRNA only in skeletal and cardiac muscle, with skeletal
expression being greater than that of cardiac. In the current study,
changes in transgene expression with age were examined. Transgenic
(i.e., human) and endogenous IGF-I levels in serum and heart
homogenates were measured by IRMA or radioimmunoassay at 10, 20, and 32
wk of age (Fig. 1
A, B). Human IGF-I (hIGF-I) was detected in transgenic serum
at every time point; serum from control mice contained no detectable
hIGF-I. The serum level of endogenous IGF-I declined with age in both
control and transgenic mice. There was no statistically significant
difference in endogenous IGF-I levels between transgenic and control
serum samples at any age, implying that the SIS2 transgene was not
repressing expression of the endogenous IGF-I gene. Total (human+mouse)
serum IGF-I was not significantly different between transgenics and
controls at any time point.
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As with serum, hIGF-I was detected in SIS2 hearts at each time point, but not in control hearts. The level of endogenous IGF-I declined with age in both control and transgenic hearts. There was no statistically significant difference in the endogenous IGF-I level between control and transgenic heart homogenates at any age, suggesting that the transgene's expression was not repressing that of the endogenous IGF-I gene. However, total heart IGF-I was significantly increased ~threefold by 10 wk of age in transgenic mice compared to controls (29.9±4.4 vs. 11.8±3.2 ng/mg, P<0.003). This difference increased to fivefold by 20 wk of age (42.7±5.5 vs. 8.3±2.3 ng/mg, P<0.0001). Overall, these data indicate that the SIS2 transgene induces its phenotype primarily through enhanced local, cardiac IGF-I expression.
The SIS2 mouse develops cardiac hypertrophy
To determine the extent to which the SIS2 transgene is able to
induce cardiac hypertrophy, cardiac mass and tibial length were
measured in control and SIS2 mice at 10, 20, and 32 wk of age. Cardiac
mass (Fig. 1C
) was significantly greater in transgenic mice
by 10 wk (131.8±2.2 vs. 112.5±3.4 mg, P<0.0001), with the
increase over controls widening until 20 wk of age (150.3±2.7 vs.
125.4±4.0 mg, P<0.00001). Cardiac mass/tibial length (Fig. 1D
) was significantly greater in SIS2 mice by 10 wk
(7.22±0.11 vs. 6.22±0.17 mg/mm, P<0.0001), increasing
until 20 wk of age (7.95±0.15 vs. 6.72±0.19 mg/mm,
P<0.00001). The SIS2 transgene is able to induce cardiac
hypertrophy early in life and stimulates continued enlargement
throughout life.
IGF-I is initially beneficial, but ultimately detrimental to
systolic function
Having established that the SIS2 transgene can induce
cardiac hypertrophy, we then examined the long-term effect of IGF-I on
systolic function (Fig. 2
A). Eight SIS2 mice and eight control littermates were
subjected to aortic-pulsed Doppler measurements in a longitudinal
study. Data were collected at 10, 20, 32, and 52 wk of age. Peak aortic
outflow velocity, a measure of systolic performance, was significantly
greater (111.9±6.2 vs. 87.6±3.8 cm/s; P<0.02) in the
transgenics at 10 wk compared to controls. This benefit, however, was
not maintained; transgenic peak aortic outflow velocity was not
significantly different from controls at 20 or 32 wk and was
significantly reduced (95.3±4.0 vs. 112.1±4.9 cm/s;
P<0.05) by 52 wk compared to controls. Heart rates were not
significantly different between control and transgenic animals at any
time point (Table 1
). Thus, IGF-I expression provided a temporary systolic performance
benefit early in life, but continued expression led to compromised
performance.
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SIS2 mice exhibit reduced left ventricular early/atrial peak
filling velocity ratios
The accretive gain in cardiac mass and transient increase in peak
aortic outflow velocity observed in SIS2 mice compared to controls
might be explained by a steady degradation of left ventricular
diastolic function. To test this hypothesis, early/atrial peak filling
velocity ratios measured by transmitral pulsed Doppler were examined
(Fig. 2B
). E/A peak velocity ratios were consistently lower
in SIS2 mice than in controls. When all time points were considered
simultaneously, SIS2 mice demonstrated a significant reduction in
early/atrial peak filling velocities (P<0.03). Heart rates
were not different between groups at any time point. Thus, it is likely
that the long-term effect of a loss of left ventricular compliance or
impairment of relaxation is at least partially responsible for the
systolic performance changes present in the SIS2 mouse.
Histological findings in SIS2 mice
Having observed that the SIS2 transgene provides a short-term
systolic performance benefit but a long-term detriment, we searched for
structural differences between transgenic and control mice that could
provide a rationale for the functional effect. Hearts from 52-wk-old
transgenic and littermate control mice were sectioned and immunostained
for sarcomeric myosin (Fig. 3
). Control heart sections displayed uniform myosin expression. A few
punctate regions lacking myosin expression were determined to be nuclei
on counterstaining with Hoechst 33258. These findings contrasted
sharply with those of the transgenic heart sections. In these, myosin
expression was intermittent; large areas were devoid of myosin protein.
Most of these nonmyosin regions were not nuclei, as they failed to
stain with Hoechst 33258. Sections from transgenic hearts also revealed
dramatic myofiber hypertrophy; myofiber disorganization was evident in
some transgenic sections. Myofiber hypertrophy and disorganization are
common elements of pathological cardiac hypertrophy. Regions of the
transgenic sections that failed to stain with sarcomeric myosin
antibody or Hoechsht 33258 might be explained by yet another feature of
pathological hypertrophy, interstitial fibrosis.
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To test the hypothesis that these regions contained collagen, all mice
from the longitudinal study were killed at 72 wk of age and their
hearts were fixed for histological examination. Upon dissection,
transgenics displayed wide variability in cardiac mass compared to
controls (188.4±22.0 mg vs. 151.7±14.4 mg, P<0.05). Some
72 wk transgenic mouse hearts exhibited overt organ pathology
(Fig. 4A
). Individual myofibers from some transgenic heart sections
were hypertrophied severalfold compared to controls (Fig. 4B
), but this varied with the degree of cardiac hypertrophy
in each mouse. To determine the extent of interstitial fibrosis,
sections from each longitudinal study heart were stained with Sirius
red, which binds collagen quantitatively. Transgenic hearts (72-wk-old)
demonstrated a significantly greater percentage of fibrosis per
complete cross section (12.0±2.0 vs. 3.3±0.5%, P<0.01)
compared to controls (Fig. 4C
). Thus, it is likely that the
nonmyosin, nonnuclear regions in sections from 52-wk-old transgenic
also contained collagen. The significantly decreased systolic
performance seen in aged SIS2 mice corresponded with their increased
cardiac interstitial fibrosis.
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We also examined young SIS2 mice to determine whether the converse held true. Sirius red-stained heart sections from 15-wk-old transgenic mice trended toward increased fibrosis compared to controls, but did not achieve statistical significance (7.8±1.2 vs. 4.4±0.5%, P<0.08). Myofiber disorganization was not evident and myofiber hypertrophy was marginal in 15-wk-old transgenic mice. Although a cause-and-effect relationship cannot be proved, erosion of the temporary benefit in systolic performance conferred by the SIS2 transgene closely paralleled the development of interstitial fibrosis.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. We present evidence that cardiac expression of
IGF-I in the absence of significantly increased serum IGF-I is
sufficient to initiate and promote an analog of physiologic cardiac
hypertrophy, which eventually progresses to a pathological state. The
phenotypic progression of the SIS2 mouse closely parallels that of the
mammalian heart in hypertension. In the early stages of mammalian
hypertension, individual myocytes increase the number of myofibers they
contain in an attempt to normalize the increased systolic pressure
applied to them. Grossly, the heart begins to develop a concentric
hypertrophy of the left ventricle. A microscopic examination of the
heart at this stage reveals hypertrophy of well-organized myocytes, but
fibrosis and myofiber disorganization are not yet evident. From a
functional standpoint, the heart effectively compensates for its
high-pressure operating environment, as there is no loss in cardiac
output. In the present study, the SIS2 mouse developed statistically
significant increases in cardiac mass and cardiac mass/tibial length by
10 wk of age, but neither myofiber disorganization nor statistically
significant fibrosis had developed by 15 wk. The hypertrophy in 10 wk
SIS2 mice actually provided an increase in systolic performance when
compared to controls. Thus, young SIS2 mice present an analog of
physiologic cardiac hypertrophy. Were pressure overload actually
present, these findings might well be classified as compensated
pathologic hypertrophy, and it is this early phenotypic stage of
hypertensive heart disease for which the young SIS2 mouse may be an
effective model. With severe or even mild but persistent hypertension, the mammalian heart will undergo further hypertrophy until the phenotype progresses to a more pathological state. Grossly, this is characterized by pronounced concentric hypertrophy of the left ventricle. Other chambers may reveal pathological anatomic changes as well. Microscopically, the pathologically hypertrophied heart reveals prominent hypertrophy of individual myocytes, disorganization of myofibers, and increased interstitial fibrosis. Despite the increased heart mass and consequent increase in oxygen and metabolite consumption, cardiac output actually declines. Often this is due to a loss of ventricular compliance. In effect, the thicker ventricular wall and its increased collagen content lead to less efficient diastolic filling. In a similar fashion, the SIS2 mouse exhibits a progressive development of pathological features as the animal matures. The statistically significant increases in cardiac mass and cardiac mass/tibial length that SIS2 mice exhibit by 10 wk of age become more pronounced with age. Histological examination of 72-wk-old SIS2 mice revealed hypertrophy of individual myocytes and significantly increased interstitial fibrosis when compared to controls. Despite the increased cardiac hypertrophy, the SIS2 transgenic mouse's systolic function steadily deteriorates from 10 wk of age (if not earlier) until it is significantly worse than that of control mice (at 52 wk). Although no relative decrease over time was evident, early/atrial peak filling velocity ratios were also significantly reduced in SIS2 transgenic mice compared to controls, indicating that diastolic function may also be compromised in this animal model. The IGF-I expression pattern and the phenotype progression observed in the SIS2 mouse may make this animal an informative model for pressure overload-induced cardiac hypertrophy.
No model is perfect, but we believe the limitations inherent in the
SIS2 mouse model are outweighed by its potential utility. Given the
increase in skeletal muscle mass seen in the SIS2 mouse
(23)
, it could be argued that increased metabolic demand
by peripheral tissues is the primary factor driving the development of
cardiac hypertrophy. However, the presence or absence of the SIS2
transgene was the only statistically significant factor in determining
cardiac mass after normalizing cardiac mass to lean body mass, a metric
dominated by skeletal muscle mass (data not shown). Combined with the
statistically significant increase in hIGF-I detected in the SIS2 mouse
heart, these data suggest that the transgene exerts a direct
hypertrophic effect on cardiac tissue.
If present, changes in afterload resistance might account for the
majority of this study's reported differences in systolic performance
between SIS2 and control mice. We did not measure systemic aortic blood
pressure on a longitudinal basis in this study, as this would have
required repeated catheterization. The possible presence of vascular
hypertrophy was examined as part of the original characterization of
the SIS2 mouse, but no evidence of this phenomenon was found. This
information is corroborated by the lack of transgene mRNA expression in
smooth muscle tissue (23)
and by the lack of significant
circulating hIGF-I in the current study.
Peak aortic outflow velocity is also sensitive to changes in preload
and heart rate. Heart rate was not significantly different among
transgenic and control animals at any time point in this study (Table 1)
. This study does present evidence of decreased early/atrial peak
filling velocity ratios in SIS2 mice compared to controls, suggesting
that diastolic function is compromised in the transgenic animals.
However, it is important to note that the greatest deficit in
transgenic E/A peak velocity ratios compared to control values occurs
at 10 wk of age, when the transgenic animals' peak aortic outflow
velocity is 128% of the control value. At 52 wk of age, peak aortic
outflow velocity of SIS2 mice is only 85% of that of control mice, but
the relative difference between transgenic and control E/A peak
velocity ratios is essentially unchanged from the 10 wk time point.
This lack of correlation between the relative decline in peak aortic
outflow velocity and the relative E/A peak velocity ratio strongly
suggests that preload changes alone are unlikely to account for the
erosion of systolic performance in the SIS2 transgenic mouse.
The well-documented ability of IGF-I to improve cardiac performance, at
least temporarily, in clinical (15)
and experimental
(12
, 25)
cardiac pathologies has sparked much interest in
the use of this hormone as a novel therapy in the failing heart. Here
we examined the cardiac effect of local IGF-I expression throughout the
majority of an animal model's life span. This long-term perspective
has proved to be of critical importance. We confirmed the short-term
benefit in systolic performance After IGF-I administration reported in
other studies. However, we have determined that this benefit is
transient, and that with continued exposure to IGF-I, the heart
develops pathological features including reduced systolic performance
and marked interstitial fibrosis. Our demonstration that IGF-I
ultimately compromises cardiac function and induces undesirable
cellular changes in the heart may limit the therapeutic potential of
chronic IGF-I administration. Consequently, the potential
cardiovascular benefits of IGF-I must be carefully balanced against the
potential dangers inherent in stimulation by this growth factor.
Considering our findings, limiting temporal exposure to IGF-I seems the
most efficacious means of delivering the potential benefits of IGF-I
while avoiding its deleterious side effects.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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