(Hypertension. 1999;34:1215.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Influence of Age on Contractile Response to Insulin-Like Growth Factor 1 in Ventricular Myocytes From Spontaneously Hypertensive Rats
From the Department of Physiology (J.R.), University of North Dakota, Grand Forks, and the Departments of Physiology (L.J., R.A.B.) and Internal Medicine (J.R.S.), Wayne State University School of Medicine, Detroit, Mich.
Correspondence to Ricardo A. Brown, PhD, Department of Physiology, Wayne State University School of Medicine, 540 E Canfield Ave, Detroit, MI 48201. E-mail rbrown{at}med.wayne.edu
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Abstract—Evidence suggests a pathophysiological role of insulin-like growth factor 1 (IGF-1) in hypertension. Cardiac function is altered with advanced age, similar to hypertension. Accordingly, the effects of IGF-1 on cardiac myocyte shortening and intracellular Ca2+ were evaluated in hypertension at different ages. Ventricular myocytes were isolated from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), aged 12 and 36 weeks. Mechanical and intracellular Ca2+ properties were examined by edge-detection and fluorescence microscopy. At 12 weeks, IGF-1 (1 to 500 ng/mL) increased peak twitch amplitude (PTA) and FFI changes (
FFI) in a dose-dependent manner in WKY myocytes, with
maximal increases of 27.5% and 35.2%, respectively. However, IGF-1
failed to exert any action on PTA and FFI in the age-matched SHR
myocytes. Interestingly, at 36 weeks, IGF-1 failed to exert any
response in WKY myocytes but depressed both PTA and FFI in a
dose-dependent manner in SHR myocytes, with maximal inhibitions of
40.5% and 16.1%, respectively. Myocytes from SHR or 36-week WKY were
less sensitive to norepinephrine (1 µmol/L) and KCl
(30 mmol/L). Pretreatment with nitric oxide synthase
inhibitor
N
-nitro-L-arginine methyl
ester (L-NAME, 100 µmol/L) did not alter the IGF-1–induced
response in 12-week WKY myocytes but unmasked a positive action in
12-week SHR and 36-week WKY myocytes. L-NAME also significantly
attenuated IGF-1–induced depression in 36-week SHR myocytes. In
addition, the Ca2+ channel opener Bay K8644 (1
µmol/L) abolished IGF-1–induced cardiac depression in 36-week SHR
myocytes. Collectively, these results suggest that the IGF-1–induced
cardiac contractile response was reduced with advanced age as well as
with hypertension. Alterations in nitric oxide and intracellular
Ca2+ modulation may underlie, in part, the resistance to
IGF-1 in hypertension and advanced age.
Key Words: insulin growth factor • hypertension, essential • aging • myocytes • calcium
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Introduction |
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Hypertension, a major risk factor for stroke and myocardial infarction, often leads to cardiac hypertrophy and electromechanical abnormalities such as prolonged action potential and contraction duration. Clinical and experimental investigations have shown an association between insulin resistance, hyperinsulinemia, and hypertension.1 2 However, the exact nature of this relation remains to be established. Biophysical and biochemical evidence has also suggested that myocardial structure and function alter with advanced age in a manner similar to hypertension, although aging itself may not be sufficient to induce cardiac hypertrophic response and hypertension.3 4 It is believed that individual myocyte function may be preserved with developed age but that myocyte apoptosis and replacement by extracellular matrix may contribute substantially to the decrement in active cardiac contractile function in aging.4 5 Recent evidence has also suggested that insulin resistance plays a key role in cardiovascular abnormalities in aging,2 6 although the underlying mechanisms have not been elucidated.
Insulin-like growth factor (IGF-1), a 70–amino acid basic peptide, is an essential growth factor for cellular proliferation and differentiation. It can be synthesized and act as an autocrine/paracrine factor, exerting both inotropic and growth effects in the heart.7 8 Unlike insulin, 95% of the circulating IGF-1 is bound to IGF-1 binding proteins (IGFBPs), mainly IGFBP-3. These IGFBPs are believed to mediate the actions of IGF-1 in a cell- and tissue-specific manner.9 IGF-1 has been shown to mediate multiple physiological as well as pathophysiological responses in the cardiovascular system.2 9 IGF-1 stimulates protein synthesis10 and participates in the initiation and development of left ventricular hypertrophy.11 12 IGF-1 has also been reported to increase inositol 1,4,5-tris-phosphate levels,13 activate tyrosine kinase, tyrosine kinase phosphatase, phosphatidylinositol-3 kinase, and protein kinase C,2 14 15 16 and enhance myocardial contraction and intracellular Ca2+ level or sensitivity,16 17 18 19 suggesting a possible role in normal cardiac mechanical function. However, recent studies have revealed a positive correlation between circulating IGF-1 level and hypertension.20 21 Both IGF-1 mRNA and protein levels have been reported to be elevated in the heart in parallel with the development of hypertension.11 22 With the use of rat heart papillary muscles, we recently observed that hypertension and advanced age significantly attenuated IGF-1–induced myocardial force-generating capacity,23 indicating that IGF-1 may play a role in the altered myocardial function under hypertension and/or advanced age. To date, the underlying mechanism of altered myocardial response has not been elaborated.
The aims of the present study were to investigate the cardiac contractile response of IGF-1 in single ventricular myocytes isolated from hypertensive and normotensive rats at a young age (12 weeks) and relatively old age (36 weeks). We also sought to study the mechanism(s) of action underlying IGF-1–induced cardiac contractile action. Spontaneously hypertensive rats (SHR), a model for human essential hypertension, and age-matched normotensive Wistar-Kyoto rats (WKY) were used. The SHR develops left ventricular hypertrophy in response to sustained elevated arterial blood pressure and total peripheral resistance. This model is also characterized by defects in insulin/IGF-1 actions similar to those observed in essential hypertension.2 24 Development of ventricular dysfunction also appears to increase with age or the duration of hypertension.25 26 Thus, the present study was designed to evaluate the effect of IGF-1 on cardiac contractility/Ca2+ metabolism in WKY and SHR at an advanced age (36 weeks).
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Methods |
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Animals
The experimental procedures were approved by the Wayne State University Animal Investigation Committee. To determine whether hypertension and advanced age affect the cardiac contractile response to IGF-1, adult male WKY and SHR were obtained from Taconic Farms (Germantown, NY) at 4 weeks of age and maintained through 12 or 36 weeks of age. The animals were individually housed in a temperature-controlled room under a 12-hour light/dark illumination cycle and were allowed standard rat chow and tap water ad libitum. Systolic blood pressures and body weights were obtained on a weekly basis by using the tail-cuff method and a standard laboratory balance, respectively.26
Cell Isolation
At the end of the experimental period, single
ventricular myocytes were enzymatically dissociated from
the rat hearts by the method described.19 Isolated
myocytes were plated on glass coverslips and maintained in a serum-free
medium at 37°C. Mechanical properties remained relatively stable for
12 to 24 hours. Only rod-shaped myocytes with clear edges were selected
for study.
Cell Shortening/Relengthening
Mechanical properties of ventricular myocytes were
assessed by a video-based edge-detection system.19
Coverslips with cells attached were placed in a chamber mounted on the
microscope stage and superfused (30°C) with a buffer containing
(mmol/L) NaCl 131, KCl 4, CaCl2 1,
MgCl2 1, glucose 10, and HEPES 10, at pH 7.4. The
cells were field-stimulated at a frequency of 0.5 Hz. Shortening of the
myocytes was detected at both longitudinal edges. Cell shortening and
relengthening were assessed by the following indices: peak twitch
amplitude (PTA), time to 90% peak shortening (TPS), time to 90%
relengthening (TR90), and maximal velocities of
shortening (+dL/dt) and relengthening (-dL/dt).
Intracellular Fluorescence Measurement
A separate cohort of myocytes was loaded with fura 2-AM
(0.5 µmol/L) for 15 minutes at 30°C, and fluorescence
measurements were recorded with a dual-excitation
fluorescence photomultiplier system as
described.19 Fluorescence emissions were detected
between 480 and 520 nm after first illuminating cells at 360 nm for 0.5
seconds and then at 380 nm for the duration of the recording
protocol. The 360-nm excitation scan was repeated at the end of the
protocol, and an interpolated signal was calculated and used to
calculate the 360/380 ratio as fura 2 fluorescence intensity
(FFI).
Experimental Protocols
Myocytes were allowed to contract at a frequency of 0.5 Hz over
5 minutes to ensure steady state before superfusion with IGF-1. In some
studies, the nitric oxide synthase (NOS) inhibitor
N-nitro-L-arginine
methyl ester (L-NAME, 100 µmol/L, Sigma Chemical Co) was
incubated with the muscles for 15 minutes before IGF-1 addition.
Myocytes with rundown >10% in PTA over the first 5 minutes were not
studied further. The maximal response of IGF-1 was achieved within 4
minutes and remained steady for >20 minutes. Therefore, all the
measurements were taken after a 5-minute exposure to this hormone.
Data Analysis
Data are presented as mean±SEM. Differences between and
within groups were evaluated by 2-way ANOVA with repeated measures
(SYSTAT). A Tukey test was used as a follow-up for the multiple
comparisons. To determine significant differences in the repeated
measures factor (concentration of IGF-1), the "within-subjects"
mean square (MS) error and df error terms from the
parent ANOVA were used. To determine significant differences between
strains at a given concentration of IGF-1, the "between-subjects"
MS error and df error terms from the parent ANOVA were used.
Statistical significance was considered to be P<0.05.
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Results |
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General Features of WKY and SHR
The impact of hypertension and advanced age on blood pressure and body, liver, and kidney sizes are shown in Table 1. As expected, SHR exhibited a significantly elevated systolic blood pressure and a lower body weight compared with their WKY counterparts throughout the course of the study. Advanced age did not alter the blood pressure. Hypertension at an early stage (12 weeks) had no effect on the size of liver and kidney. However, sustained hypertension led to hepatomegaly and renal hypertrophy in SHR compared with their age-matched WKY counterparts. The size of liver and kidney were actually reduced with advanced age, which might be due to an increased body weight.
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Baseline Mechanical Properties of Ventricular Myocytes
Sustained hypertension tended to lead to cardiac
hypertrophy. Ventricular myocytes isolated from
36- but not 12-week SHR hearts exhibited considerably larger dimension
(either cell length or surface area) than did WKY myocytes. Advanced
age alone had little effect on cell dimension. Neither cell length nor
surface area was affected by IGF-1 exposure (data not shown). Myocytes
isolated from 12-week animals displayed a similar extent of shortening
capacity, as indicated by PTA. However, PTA was significantly greater
in myocytes from 36-week SHR compared with those from age-matched WKY.
The enhanced ability to shorten in older SHR myocytes was associated
with increased maximal velocities of shortening and relengthening
(±dL/dt). Interestingly, the myocyte shortening capacity decreased
with advanced age. The shortening and relengthening durations (TPS and
TR90) were not affected by early stage of
hypertension and were also reduced with advanced age. Moreover,
compared with the age-matched WKY myocytes, myocytes from older SHR
exhibited a prolonged TPS along with a normal
TR90 (Table 2).
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Effects of IGF-1 on Myocyte Shortening in WKY and SHR
Myocytes
Representative traces depicting typical effects of
IGF-1 on cell shortening are shown in Figure 1. IGF-1 (500 ng/mL) significantly
increased PTA in myocytes from 12-week WKY but not SHR (Figure 1A). At the end of a 5-minute exposure to this concentration of
IGF-1, PTA was increased by 28.4% and 3.7%, with little effect on TPS
and TR90, in WKY and SHR myocytes, respectively.
IGF-1 (1 to 500 ng/mL) caused a concentration-dependent increase in PTA
in myocytes from young WKY but not SHR, with a maximal response of
27.5% (Figure 1C). The threshold was between 1 and 10 ng/mL.
Higher concentrations of IGF-1 (to 1000 ng/mL) did not induce further
increase of PTA. By contrast, representative traces in
Figure 1B show that IGF-1 (500 ng/mL) significantly depressed
PTA in myocytes from 36-week SHR but not WKY. IGF-1 caused a
concentration-dependent depression in PTA in myocytes from older SHR
but not WKY, with a maximal inhibition of 40.5% (Figure 1C).
The threshold of the depressive action was also between 1 and 10 ng/mL.
These data indicate that the IGF-1–induced cardiac contractile
response is altered by hypertension and advanced age.
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) or SHR (
) myocytes of both age groups. Data
are presented as percent change in PTA from the respective
control value. The number of muscles is given in parentheses.
*P<0.05 vs control; #P<0.05 vs WKY
group.For comparison with IFG-1, the effect of norepinephrine (NE, 1 µmol/L) and KCl (30 mmol/L) on myocyte shortening was also examined in these myocytes. Both agonists significantly increased PTA to a much greater extent in myocytes from both WKY and SHR hearts. The responsiveness to both agonists decreased or showed a tendency to decrease in the hypertensive state or with advanced age. Finally, insulin (100 nmol/L) exerted little action on myocyte shortening. These data underscore the differential actions of IGF-1 compared with other contractile agonists (Figure 2).
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Effects of IGF-1 on Shortening and Relengthening Duration and
Velocity
As mentioned, the baseline TPS and TR90 were
not different between myocytes from 12-week WKY and SHR; however, TPS
was significantly longer in 36-week SHR myocytes than in age-matched
WKY myocytes, whereas TR90 values were not
significantly different. Also, 36-week SHR myocytes exhibited
significantly greater velocity of both myocyte shortening and
relengthening (Table 2). IGF-1 (1 to 500 ng/mL) did not exert
any effects on the TPS and TR90 in any cell group
studied (data not shown). Consistent with its effect on PTA,
IGF-1 (500 ng/mL) increased ±dL/dt in 12-week WKY myocytes
(339±51/-360±66 versus baseline value 248±24/-223±17
µm/ms, P<0.05) and showed a tendency to decrease ±dL/dt
in 36-week SHR myocytes (318±65/-311±56 versus baseline value
378±34/-355±40 µm/ms, P>0.05).
Effect of IGF-1 on Myocyte Shortening in the Presence of L-NAME and
Bay K8644
To explore one possible mechanism of action of IGF-1, the effect
of IGF-1 was reexamined in the presence of either the NOS
inhibitor L-NAME (100 µmol/L) or voltage-dependent
Ca2+ channel opener Bay K8644 (1 µmol/L).
L-NAME alone did not modify PTA at the dose used over a duration of
>30 minutes. Bay K8644 increased PTA by 
110% in all myocyte
groups. As shown in Figure 3, L-NAME did
not affect the IGF-1–induced increase in cell shortening in 12-week
WKY myocytes, whereas L-NAME unmasked a positive contractile response
in 12-week SHR myocytes. Interestingly, the pattern of L-NAME–induced
response was not preserved with advanced age. L-NAME unmasked a
positive response in 36-week WKY myocytes that was similar to that in
12-week SHR myocytes. Moreover, the IGF-1–induced depression in
36-week SHR myocytes was significantly attenuated by L-NAME
pretreatment. The Ca2+ channel opener Bay K8644
also blocked IGF-1–induced depressive action in 36-week SHR myocytes,
whereas it had little action in 36-week WKY myocytes (Figure 3B). These data suggested that a substantial tonic nitric oxide
(NO) production may exist in hypertension and/or advanced age
and that this NO production may lead to a decreased sarcolemmal
Ca2+ channel activity.
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Effect of IGF-1 on Intracellular Ca2+
Transients
To determine whether the altered response to IGF-1 in
hypertension and/or advanced age is related to changes in intracellular
Ca2+ level, we used fura 2 to estimate changes in
[Ca2+]i in single
myocytes. The time course of the fluorescence signal decay
(fluorescence decay time [FDT]) was evaluated to assess the
rate of intracellular Ca2+ clearing. Compared
with myocytes from WKY groups, myocytes from the respective SHR groups
exhibited elevated baseline FFI (representing resting
intracellular Ca2+ level). Advanced age also
elevated the resting intracellular Ca2+ level
(Table 3). These data indicated a
potential Ca2+ overload associated with
hypertension and/or advanced age. Representative traces
in Figure 4A depict typical
IGF-1–induced responses on the electrically stimulated increase of
intracellular Ca2+ (FFI=peak FFI-baseline
FFI) in WKY and SHR myocytes. Acute IGF-1 (1 to 500 ng/mL) exposure
exerted a concentration-dependent increase of FFI in 12-week WKY but
not SHR myocytes, in a pattern similar to its effect on PTA. The
maximal increase was 35.2% at 500 ng/mL, and the threshold of action
was between 1 and 10 ng/mL. However, IGF-1 (1 to 500 ng/mL) caused a
concentration-dependent inhibition in FFI in 36-week SHR myocytes
but elicited little response in 36-week WKY myocytes. The maximal
inhibition was 16.1%, and the threshold of response was between 10 and
100 ng/mL (Figure 4). All the intracellular
Ca2+ responses achieved steady state at or before
4 minutes and recovered after a 5-minute washout. These results
indicated that the IGF-1–induced cardiac mechanical responses were
likely due to changes of intracellular free Ca2+.
However, the disproportional inhibition between PTA and FFI in
36-week SHR may indicate a shift in intracellular
Ca2+ sensitivity. Neither resting FFI nor FDT was
affected by IGF-1 in any of the groups studied (data not shown).
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Discussion |
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Pressure-overload ventricular hypertrophy is often characterized by "early" and "late" changes in the expression of certain genes and contractile protein isoforms. Previous studies have demonstrated early hypertrophic responses, including a transient expression of proto-oncogene products that regulates cardiac growth and differentiation, as well as a shift in the major forms of contractile proteins, such as
- and ß-myosin heavy chain
proteins. Increased atrial natriuretic polypeptide and
collagen type I/III have also been reported in the early stage of
cardiac hypertrophy.27 During the transition
from cardiac hypertrophy to failure, late changes such as
marked increase in collagen, fibronectin mRNA, and transforming growth
factor-ß1 levels can be detected, indicating that the expression of
specific extracellular matrix genes may contribute to fibrosis, tissue
stiffness, and impaired function.5 28 Recent evidence of
the coordinate enhancement of IGF-1 and IGF-1 receptor expression in
the early hypertensive stage suggests that IGF-1 may participate in a
cascade of events that link pressure stimuli to cellular
hypertrophy and, eventually, to cardiac mechanical
dysfunction.11 22 Hypertension and/or advanced age are
believed to be closely associated with insulin resistance and
hyperinsulinemia.2 6 Although
evidence has suggested that insulin/IGF-1, per se, may not play a role
in hypertension, insulin/IGF-1 resistance, under some circumstances,
may contribute to the pathogenesis of hypertension (or similar
cardiovascular abnormalities with advanced age), in a
manner similar to that found with other
pathophysiological factors, such as salt and its
effect on the renin-angiotensin system.2 24
Resistance in myocardial contractile response to IGF-1, a cardiac
autocrine/paracrine peptide that closely resembles insulin, also exists
in hypertension and advanced age.23 The present
investigation lends further support to the notion of IGF-1 resistance
in hypertension and/or advanced age. In the present study,
sustained hypertension but not advanced age triggered myocyte
hypertrophy, although both caused myocyte mechanical
dysfunction. IGF-1 exerted positive cardiac contractile responses in
myocytes from young WKY but not the age-matched SHR group. However,
this IGF-1–induced positive response was abolished at an older age and
reversed to a negative inotropic response in myocytes from 36-week SHR
animals. IGF-1 has been demonstrated to improve cardiac function by enhancing myocardial contractility and decreasing peripheral vascular resistance under both physiological and pathological conditions.12 16 17 18 19 29 30 Although IGF-1 may enhance cardiac contractility through an increase in contractile protein synthesis, several intracellular signaling pathways related to IGF-1 have also been implicated, including tyrosine kinase, tyrosine kinase phosphatase, phosphatidylinositol-3 kinase, and protein kinase C.2 14 15 16 Activation of one or more of these intracellular signaling pathways may be directly related to the elevation of intracellular Ca2+18 19 or intracellular Ca2+ sensitivity.16 30 Membrane ion channels have also been implicated in the IGF-1–related modulation of cardiac function. IGF-1 stimulates T-type Ca2+ current density in cardiac myocytes through altered channel gene expression.31 Long-term administration of IGF-I has also been found to regulate cardiac K+ channel expression in neonatal rat ventricular myocytes. In vitro evidence has provided invaluable information because of the difficulty of establishing in vivo whether myocardial functional changes are attributed exclusively to IGF-1 or are dependent on its impact on the other organs and loading conditions.
Recent studies have shown resistance to IGF-1 in experimental animal
models, such as those involving diabetes and
hypertension.19 23 32 33 Little information is available
regarding the cardiac effects of IGF-1 in hypertension and/or advanced
age. We and other investigators have previously demonstrated that IGF-1
increases intracellular Ca2+ in concert with
myocardial contraction and myocyte shortening.17 18 19
Results from the present study have demonstrated similar effects in
young WKY animals. However, this positive response was not seen in
age-matched SHR or older WKY groups. Older SHR myocytes even revealed
the depressive effect of IGF-1 on PTA and FFI. The attenuated or
reversed responsiveness to IGF-1 in hypertension and/or advanced age
may be related to the reduced myocardial IGF-1 receptors or
postreceptor responses under these conditions. However, there are
several reports of an increased IGF-1 receptor mRNA and protein levels
in various models of hypertension, including human essential
hypertension.9 21 22 34 35 An elevation in vascular wall
stress is believed to be an important predisposing factor for the
elevated gene expression of IGF-1, IGF-1 receptor, and other growth
factor receptors in the cardiovascular
system.35 On the other hand, high levels of circulating
IGF-1/insulin, commonly seen in hypertension, may result in a
downregulation of IGF-1/insulin receptor binding or
effectiveness.21 The precise mechanism accounting for the
dissociation between the increased IGF-1 receptor expression and the
reduced mechanical response in hypertension is still not clear. The
differential response between IGF-1 and insulin seen in the present
study may be related to an altered expression of IGF-1/insulin hybrid
receptors found in insulin-resistant states such as
hypertension.21
NO has been implicated in the endogenous control of myocardial contractility. Constitutive NOS is present in cardiac myocytes and has been demonstrated to be regulated by a ß-adrenergic signaling pathway.36 Constitutive NOS activation is frequency dependent in ventricular myocytes,37 as NO production increases when myocytes are continuously stimulated to contract. IGF-1 is known to stimulate NO production in various tissue or cell types.38 39 Data from the present study indicate that NO may be involved in the IGF-1–induced cardiac contractile response. In young animals, NOS inhibition failed to modify IGF-1–induced positive action in WKY myocytes, whereas it unmasked a positive contractile response in SHR myocytes. However, in the older groups, NOS inhibition unmasked a positive response in WKY myocytes and blocked the IGF-1–induced depressive action in SHR myocytes. These findings indicate altered NO mechanisms in hypertension and/or advanced age. The fact that Bay K8644 blocked the IGF-1–induced myocardial depression in SHR myocytes may also support the hypothesis of cardiac NO overproduction in hypertension and/or advanced age,40 41 because NO is known to inhibit the voltage-dependent Ca2+ channel, and this inhibition leads to a negative inotropic response.42 43 However, the methods used in the present study were unable to detect any disparity in NO production under hypertension and/or advanced age. Direct measurement of NOS activity in cardiac myocytes is needed to better understand the mechanism underneath the resistance to IGF-1 in these pathophysiological states. Last, the reduced response to IGF-1 and other agonists such as NE may also be associated with the existence of an intracellular Ca2+ overload or diminished ß-adrenergic activity in hypertension and/or advanced age.3
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Acknowledgments |
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This study was supported in part by National Institutes of Health/National Heart, Lung, and Blood Institute grant GM-08167 and National Institute of Mental Health/Minority Institution Research Development Program grant MH-47181 to Dr Brown. The authors wish to thank Nidas Undrovinas for skillful technical assistance. IGF-1 was provided by Genentech Inc.
Received October 26, 1998; first decision November 23, 1998; accepted July 23, 1999.
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