(Hypertension. 1996;27:636-642.)
© 1996 American Heart Association, Inc.
Articles |
Cardiac Insulin-like Growth Factor I and Growth Hormone Receptor Expression in Renal Hypertension
From the Department of Physiology, Institute of Physiology and Pharmacology (G.G., P.F., A.W.), and the Research Center for Endocrinology and Metabolism, Department of Internal Medicine (C.B., B.G., J.I.), Göteborg University, Sweden.
Correspondence to Gregor Guron, Department of Physiology, Institute of Physiology and Pharmacology, Göteborg University, Medicinaregatan 11, S-413 90 Göteborg, Sweden. E-mail gregor.guron@fysiologi.gu.se.
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Abstract |
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Abstract The aim of the present study was to investigate the role of insulin-like growth factor I in the development of cardiac hypertrophy in two-kidney, one clip hypertension by relating growth hormone receptor and insulin-like growth factor I receptor mRNA levels to insulin-like growth factor I gene transcription using a solution hybridization/RNase protection assay. Two-kidney, one clip hypertension was induced in male Wistar rats, and experiments were performed 2, 4, 7, and 12 days after surgery. Systolic blood pressure was elevated 2, 7, and 12 days after clipping (P<.001). Left ventricular weights were increased 2, 4, 7, and 12 days after surgery (P<.01). Associated with the rise in blood pressure, left ventricular insulin-like growth factor I mRNA was increased 2, 7, and 12 days after surgery (P<.01). Furthermore, growth hormone receptor and insulin-like growth factor I receptor gene expression increased specifically in the left ventricle of renal hypertensive rats (P<.05 and P<.001, respectively). Left ventricular growth hormone receptor mRNA peaked 7 days after induction of renal artery stenosis. These results show that insulin-like growth factor I, growth hormone receptor, and insulin-like growth factor I receptor mRNA increase in the pressure-overloaded left ventricle of two-kidney, one clip rats, suggesting a role for insulin-like growth factor I and the growth hormone/insulin-like growth factor I axis in the development of cardiac hypertrophy.
Key Words: rat • renal hypertension • hypertrophy, cardiac • insulin-like growth factor I • growth hormone
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The LV adapts rapidly to an increased systemic pressure load, as in 2K1C renal hypertension, by increasing its ratio of wall thickness to lumen, thereby reducing systolic wall stress.1 2 However, the conversion of a mechanical stimulus into a receptor/ion channel activation that induces various second-messenger systems, ultimately resulting in cardiac growth, is not fully understood. Although circulating growth factors, including Ang II2 and catecholamines,3 4 are important in the hypertrophic process, there is now ample evidence to suggest a role for autocrine/paracrine mechanisms within the myocardium, as has been shown for the RAS5 6 7 8 9 and proto-oncogenes c-fos, c-jun, and c-myc.10 11 Recent data have provided in vivo evidence for a potential role of tissue IGF-I in the developing process of cardiac hypertrophy12 13 14 15 16 17 18 and have shown that induction of IGF-I gene transcription may be linked to an acute increase in systolic wall stress.14 16 18 Temporally, elevated IGF-I gene expression coincides with the development of cardiac hypertrophy, with peak values occurring some days after the onset of the hemodynamic load, clearly separating IGF-I from immediate/early growth factors.12 13 14 15 16 17 18 Interestingly, GH-R gene expression was elevated in the acutely volume-overloaded RV of ACF-operated rats,16 suggesting that GH may potentiate cardiac IGF-I synthesis on the tissue level independently of circulating hormone levels.
To gain enough biological effect by IGF-I, it is necessary that its receptor also is concurrently expressed on the cell surface. The IGF–I-R has been shown to be expressed transiently in fetal and neonatal myocardium, decreasing rapidly after birth,19 20 as well as in a model of cardiac ischemia during tissue repair in adult rats.21 There is, however, a lack of in vivo experiments to determine the role of IGF–I-R in cardiac growth processes in adult animals in relation to an activation of its ligand. The aim of the present study, therefore, was to further investigate the role of IGF-I in the initial process of cardiac hypertrophy induced by a pressure load.
GH-R and IGF–I-R mRNA levels were related temporally to IGF-I gene expression and the development of cardiac hypertrophy in hearts of 2K1C rats by means of a solution hybridization/RNase protection assay.
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Methods |
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Animals and Surgical Procedures
2K1C renal hypertension was induced in male normotensive Wistar rats (Möllegaard Breeding Center Ltd, Ejby, Denmark) weighing about 190 g by placement of a silver clip (diameter, 0.18 mm) around the left renal artery through a flank incision, leaving the right kidney intact. Sham-operated control rats underwent a similar procedure, with manipulation of the left renal artery but without permanent application of a clip. Anesthesia was induced by the short-lasting barbiturate methohexital sodium (Brietal, Eli Lilly and Co) at a dose of 75 mg/kg IP. Throughout the study period, rats were kept in rooms with a 12-hour light/dark cycle and a constant temperature of 25°C. Standard rat chow and water were supplied ad libitum.
Experiments were performed on groups of 8 2K1C and 5 sham-operated rats 2, 4, 7, and 12 days after surgery. On the day of experimentation, rats were weighed and systolic blood pressure and heart rate were measured by tail-cuff plethysmography (Narco BioSystems). Animals were then anesthetized with methohexital sodium, and hearts were excised. The atria and great vessels were trimmed away, and the ventricles were carefully separated and weighed before being frozen in liquid nitrogen and stored at -80°C until assay. Cardiac IGF-I, IGF–I-R, and GH-R mRNA were quantified by means of a solution hybridization/RNase protection assay on all sham-operated rats and 6 of 8 randomly selected 2K1C hearts. IGF–I-R mRNA was not quantified in the RV. All experiments were approved by the regional ethics committee in Göteborg.
Probes
Growth hormone receptor. The pT7T3 18U plasmid contains a 560-bp BamHI fragment of the rat GH-R cDNA that encodes the early part of the extracellular domain of the GH-R. The probe would therefore allow the detection of both the GH-R and GH binding protein. Antisense GH-R 35S-UTP–labeled RNA was synthesized according to the manufacturer's instructions (Promega).
Insulin-like growth factor I. A 153-bp Sma I fragment of a genomic subclone of mouse IGF-I (corresponding to exon 3 by analogy to human IGF-I) subcloned into a pSP64 plasmid was used as a template for probe synthesis.22 The plasmid was linearized with EcoRI and used as a template for synthesis of 35S-UTP–labeled IGF-I cRNA with SP6 RNA polymerase according to the manufacturer's instructions (Promega).
Insulin-like growth factor I receptor. The IGF–I-R RNA probe was synthesized from a 265-bp fragment of the rat IGF-I receptor cDNA subcloned into a plasmid vector, pGEM-3.20 The vector was linearized with EcoRI, and the rat IGF–I-R antisense RNA was synthesized by use of a SP6 RNA polymerase and 35S-UTP. Synthesis of the rat IGF–I-R sense RNA standard was achieved by use of BamHI for linearization of the plasmid and addition of T7 RNA polymerase.
Hepatocyte growth factor. To study the specificity of the cardiac gene expression, the levels of cardiac HGF were determined. A 650-bp rat HGF cDNA probe was labeled with 35S-UTP and synthesized by use of an in vitro transcription set according to the manufacturer's instructions (Promega) with a 1.4-kb EcoRI insert of pRBC1 in a Sac I plasmid linearized with Bgl II.
Solution Hybridization
Frozen tissue was homogenized with a
polytron in 1%
SDS, 20 mmol/L Tris-HCl (pH 7.5), and 4 mmol/L EDTA. The
homogenate was treated with proteinase K, and TNAs were
extracted with phenol-chloroform as previously
described.23 A solution hybridization assay was used to
quantify IGF-I, IGF–I-R, and GH-R mRNA.23 The probes were
hybridized to TNA samples at 70°C for 24 hours in 0.06 mol/L NaCl; 20
mmol/L Tris-HCl (pH 7.5); 4 mmol/L EDTA; 0.1% SDS; 10 mmol/L
dithiothreitol; 25% formamide; and 35S-labeled IGF-I,
IGF–I-R, or GH-R RNA probes. After the addition of 100 µg herring
sperm DNA, the samples were treated with 40 µg/mL RNase A and 2
µg/mL RNase T1 (Sigma Chemical Co). Trichloroacetic
acid–precipitated protected hybrids were then collected on
fiberglass filters (GF/C Whatman, Whatman International Ltd) and
counted in a scintillation counter. The signal was compared with a
standard curve based on known amounts of IGF-I, IGF–I-R, or GH-R mRNA.
The results were related to the DNA content in the TNA sample according
to Labarca and Paigen.24 Results are expressed in
attomoles (10-18) mRNA per microgram DNA
(amol/µg DNA).
RNase Protection
The specificity of the probes used in the
solution
hybridization assay was confirmed by separating the protected fragments
on a gel. Total RNA was prepared according to the modified method of
Chomczynski and Sacchi.25 Samples (25 to 35 µg) were
hybridized in a buffer containing 22 mmol/L Tris, 5 mmol/L EDTA, 0.6
mol/L NaCl, 0.075 mg/mL tRNA, 0.75 mmol/L dithiothreitol, 25%
formamide, 0.1% (wt/vol) SDS, 500 000 cpm 35S-labeled
antisense RNA probe, and diethyl pyrocarbonate/water up to a final
volume of 40 µL. The samples were mixed and incubated overnight at
70°C.
Single-stranded RNA was digested by addition of 300 µL
digestion
buffer containing 10 mmol/L Tris-HCl (pH 7.5), 300 mmol/L NaCl, 5
mmol/L EDTA, 40 µg/mL RNase A, and 2 µg/mL RNase T1 in
a 30-minute incubation at 37°C. After treatment with 20 µL 10% SDS
and 50 µg proteinase K for 15 minutes at 37°C, the RNA was
extracted with phenol/chloroform and precipitated with 2.5 vol ethanol,
with 10 µg tRNA as the carrier. The samples were incubated at
-20°C for 1 hour and subsequently centrifuged at
12 500 rpm for 20 minutes at 4°C. Pellets were dried and then
resuspended in a loading buffer containing 80% formamide, 15% Ficoll,
and 0.25% bromphenol blue. The protected fragments were separated by
electrophoresis on an 8 mmol/L urea/6% polyacrylamide
denaturing gel for 1.5 hours at 1000 V and then washed in 10%
ethanol/10% acetic acid for 30 minutes. After the gel was dried, it
was exposed on a PhosphoImager screen (Molecular Dynamics Inc) for 3 to
7 days. An end-labeled 
174/HaeIII DNA marker
(Promega) was used as a molecular size marker.
Statistical Analysis
Values are given as mean±SEM. The
statistical differences
between groups were analyzed by one- or two-way ANOVA
followed by Fisher's post hoc test. A value of P<.05 was
considered statistically significant.
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Results |
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Body Weight
2K1C-operated rats showed a significant reduction in body weight after surgery compared with sham-operated rats (P<.01). However, post hoc analysis showed no difference between 2K1C and sham-operated rats in body weight 2, 4, and 7 days after surgery (163±9 versus 183±11 g, 186±9 versus 207±11 g, and 188±9 versus 200±11 g, respectively). 2K1C rats had a statistically significant reduction in body weight 12 days after surgery compared with sham (190±9 versus 239±11 g, P<.01), which was most likely due to the development of malignant hypertension in 3 rats with postoperative reductions in body weight of about 50 g and blood pressures measuring >220 mm Hg. Of a total of 52 rats that underwent surgery, one death was caused by anesthesia. No deaths occurred after surgery.
Blood Pressure
Systolic blood pressure in 2K1C rats was
elevated
throughout the study period (P<.001) (Fig 1
).
However, for reasons that are unclear, there was no
statistically significant difference in systolic blood
pressures between 2K1C and sham-operated animals 4 days after
surgery (162±8 versus 146±10 mm Hg, P=NS).
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Left and Right Ventricular Weights
LVW and RVW per gram body
weight are presented in the
Table and in Fig 2. Renal hypertension
induced a pronounced increase in LVW throughout the study period
(P<.001). There was a slight increase in RVW in 2K1C
animals (P<.01), although to a much lesser extent than for
the LV (mean increases in LVW and RVW throughout the study period were
39±4% and 16±4%, respectively; P<.001). Moreover,
absolute LVW increased substantially (P<.05), while
absolute RVW remained unaltered versus sham, normotensive rats. Hence,
ratios of LVW to RVW increased substantially in 2K1C rats
(P<.001), clearly demonstrating the development of LV
hypertrophy.
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Solution Hybridization
Results from solution hybridization
experiments are shown in
the Table
and in Fig 2. Data are presented in
amol/µg DNA and
as folds of increase over sham, respectively. LV IGF-I mRNA increased
in 2K1C animals (P<.001) and was already elevated 2 as well
as 7 and 12 days after surgery. However, 4 days after surgery, LV IGF-I
mRNA levels in 2K1C rats did not reach a significant level (0.22±0.02
versus 0.14±0.01 amol/µg DNA, P=.067), which may be
a
consequence of the lack of a significant blood pressure elevation in
the 2K1C group at this particular time. RV IGF-I mRNA levels showed
some increase after the induction of renal hypertension
(P<.05) but were not significantly elevated at any time by
post hoc analysis. The increase in IGF-I gene expression was
more pronounced in the LV (folds of increase in LV and RV IGF-I mRNA
levels throughout the study period were, on average, 2.0±0.1 and
1.4±0.2, respectively; P<.05). Furthermore, GH-R and
IGF–I-R gene expression increased in the LV of 2K1C animals
(P<.05). LV GH-R mRNA levels peaked 7 days after induction
of 2K1C hypertension, whereas LV IGF–I-R gene expression was elevated
2 days after surgery. There was no induction of GH-R gene transcription
in the RV. IGF–I-R mRNA was not measured in the RV.
HGF mRNA was quantified in the LV as an unrelated control gene. LV HGF gene expression remained unchanged in renal hypertensive rats compared with normotensive control rats (0.13±0.03 versus 0.24±0.12, P=NS) and did not change over time.
RNase Protection
RNase-protected probe fragments were
analyzed on
denaturing polyacrylamide gels. For IGF-I (Fig 3A), the
undigested probe was found to be 
170 bases
long, consisting of a 153-base insert and additional polylinker bases
(lane 1). One hundred twenty bases were protected when the probe was
hybridized to RNA from the RV, LV, and liver (lanes 6, 7, and 8,
respectively), the smaller size probably reflecting a certain mismatch
between the mouse probe and rat RNA. A background transcript of
approximately 125 bases was also protected (lanes 2 through 8). This
mismatch in protected fragments on the gel could be reflected in the
results of the solution hybridization assay but would probably cause
equally high background values in both the experimental and
sham-operated groups.
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For the GH-R (Fig 3B), the
undigested probe was found to be 560 bases
long, corresponding to the insert (lane 1). Four hundred ten bases were
RNase-protected when the probe was hybridized to RNA from the RV,
LV, and liver (lanes 6, 7, and 8, respectively). The smaller protected
fragment reflects the fact that the first part of the probe is not
homologous to the rat GH-R mRNA.26
The size of the
IGF–I-R mRNA protected band (Fig 3C) was 265 bases
when the probe was hybridized to RNA from the RV, LV, and liver (lanes
6, 7, and 8, respectively).
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Discussion |
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The main findings of the present study were that IGF-I, GH-R, and IGF–I-R mRNA levels all increased in the pressure-overloaded LV in early renal hypertension. This suggests that IGF-I is involved in the development of cardiac hypertrophy and that its overexpression may be triggered by an acute elevation in systolic wall stress. These findings are in accordance with previous results in renal hypertensive rats, in which specific increases of IGF-I at both the mRNA and protein levels were demonstrated in the LV.18 In addition, the present study extends the results by Wåhlander et al18 by showing that GH-R and IGF–I-R gene transcriptions were also elevated in the LV, which in 2K1C hypertensive rats is hemodynamically challenged, indicating that cardiac IGF-I synthesis and effector pathways may be augmented primarily on the tissue level.
Although GH is the primary regulator of cardiac IGF-I gene transcription,27 28 29 our previous14 16 18 and present findings suggest mechanical factors as possible initiating stimuli. Wåhlander et al18 showed that the IGF-I protein was localized predominantly to the subendocardial layers of the pressure-overloaded LV and proposed that an increased systolic wall stress may be the eliciting stimulus for IGF-I gene transcription. We recently provided further evidence that systolic wall stress was important for cardiac IGF-I gene expression.16 Here, IGF-I mRNA was elevated only in the RV of ACF rats, in which systolic wall stress has been shown to be specifically augmented, although diastolic wall stress is elevated in both ventricles.30 31 Taken together, findings from our laboratory14 16 18 and others12 15 17 suggest that IGF-I overexpression in the heart is linked to an increase in systolic wall stress. Importantly, LV hypertrophy also occurred in ACF animals without a corresponding increase in IGF-I mRNA levels,16 demonstrating important roles for other growth factors, which may in turn be triggered by increased diastolic wall tension.
Notably, LV IGF-I gene transcription was not elevated in 2K1C rats 4 days after surgery in the present study, at which time there was no significant increase in systolic blood pressure. This finding lends additional support to the hypothesis that an increase in afterload and systolic wall stress may be an important stimulus for IGF-I gene transcription.
Local IGF-I synthesis can be stimulated by increased wall stress in other hollow organs, as in the vascular32 and urinary bladder walls,33 supporting the possibility of a mechanosensitive regulation of IGF-I synthesis by paracrine/autocrine mechanisms. The fact that IGF-I gene expression is elevated in the pressure-overloaded myocardium has been confirmed by others in different in vivo models.12 13 15 17 An increase in LV IGF-I gene expression has been found in ascending aortic banding,15 suprarenal aortic constriction,13 and abdominal aortic coarctation,12 with elevated IGF-I mRNA levels correlating temporally with the development of LV hypertrophy. Furthermore, Russel-Jones and coworkers17 demonstrated increased levels of IGF-I mRNA in the hypertrophic RV of rats exposed to chronic hypoxia, a state associated with pulmonary hypertension and an increase in RV afterload. An elevated gene expression of IGF-I has also been documented in rat hearts after experimentally induced coronary artery narrowing21 and myocardial infarction.34 In these ischemic models, an increased IGF-I transcription was associated with an enhanced local DNA synthesis, suggesting an important role for IGF-I in the regeneration of cardiac tissue after injury.
Although none of these studies have been able to directly link IGF-I to the development of hypertrophy, in vitro experiments support this possibility. IGF-I stimulates protein synthesis35 36 as well as transcription of myosin light chain-2 and troponin I36 in cultured cardiomyocytes. In addition, it was recently shown in vivo that administration of IGF-I to normotensive rats induced increases in both RVW and LVW.37
Although local stress on the tissue level may initiate cardiac IGF-I gene expression, the neurohumoral circulating milieu must also be optimal. An excess of circulating GH in rats has been associated with cardiac hypertrophy independently of significant hemodynamic changes.38 GH regulates cardiac IGF-I gene transcription,27 28 29 and GH receptor mRNA has been detected in the rat heart.26 27 39 The present study demonstrated that GH-R mRNA levels increased specifically in the pressure-overloaded LV of 2K1C renal hypertensive rats. However, it occurred somewhat later than the IGF-I gene induction (day 7 versus day 2). This finding confirmed previous results that documented an elevated GH-R gene transcription in the hemodynamically challenged RV of ACF rats,16 indicating that IGF-I synthesis may be regulated locally by GH independently of GH plasma concentration levels through an upregulation of the receptor. However, the elevated GH-R gene transcription did not precede the increase in IGF-I mRNA levels in the present study, which might have been the case if GH were an important initiator of IGF-I transcription. Instead, we speculate that GH may assist in sustaining the IGF-I synthesis. Folkow et al40 have shown in hypophysectomized rats that for a given increase in arterial blood pressure created by the 2K1C model, the subsequent degree of adaptive cardiac and vascular hypertrophy was markedly reduced compared with controls. However, substitution with thyroxin and GH almost fully restored the hypertrophic growth response, indicating a permissive role for either of these two hormones. The arguments against a direct role for GH in the initiation of IGF-I synthesis in the hemodynamically overloaded heart are first, that IGF-I gene expression is specifically elevated in the ventricle subjected to an increased systolic wall stress in 2K1C and ACF models of cardiac overload independently of circulating levels of GH16 18 and second, that evidence from other tissues has suggested a GH-independent IGF-I synthesis.22
A novel finding in the present study was the increase in LV IGF–I-R mRNA in renal hypertensive rats. Donohue et al13 measured ventricular IGF–I-R mRNA levels in DOCA-salt hypertensive rats without detecting any increase in gene expression throughout the course of the study. However, the first measurements took place rather late, 2 weeks after induction of hypertension, and at that time the IGF–I-R gene expression may already have been switched off. The induction of IGF–I-R gene expression in the present study raises the possibility of an activation of IGF-I effector pathways, optimizing the effects of the ligand, when tissue demand is high. Still, the physiological role of an increase in cardiac IGF–I-R gene expression in the hemodynamically overloaded heart needs to be evaluated further.
Most studies demonstrating an increased IGF-I gene expression in the pressure-overloaded myocardium have been experimental models with an activation of the RAS. In 2K1C rats, the principal stimulus for the development of LV hypertrophy seems to be an increase in systemic blood pressure and not an effect of high circulating Ang II levels per se, since the cardiac growth response relates temporally to the increase in blood pressure independently of circulating Ang II levels.40 In addition, Griffin et al41 showed that the increase in cardiac weight of rats chronically infused with Ang II subcutaneously was pressure dependent, since coadministration with hydralazine prevented the increase in pressure and cardiac growth. However, Ang II has also been suggested to stimulate cardiac growth independently of alterations in hemodynamics.5 42 An interaction between Ang II and IGF-I has recently been presented by Delafontaine and Lou43 in cultured vascular smooth muscle cells from rat aorta, in which Ang II caused a marked increase in IGF-I mRNA levels. Moreover, it was shown that IGF-I was an essential mediator of the mitogenic effect of Ang II on this cell type. These findings raise the question of Ang II as a possible initiator of cardiac IGF-I gene expression. However, the hypothesis that circulating Ang II may be an important stimulus for IGF-I gene expression in the LV of 2K1C hypertensive rats independent of the prevailing loading condition seems unlikely, since the rise in IGF-I mRNA levels occurred predominantly in the pressure-challenged LV. Furthermore, it has been shown that cardiac IGF-I synthesis increases in DOCA-salt hypertensive rats,13 a model with a suppressed RAS. Still, the prevailing loading condition on the tissue level may act in concert with the humoral milieu to obtain an optimal adaptive growth response. The small increase in RV weight and IGF-I mRNA in the present study may be a consequence of high circulating Ang II levels acting in synergy with an increased systolic wall stress due to Ang II–induced vasoconstriction in the pulmonary circuit.
An elevated gene expression of various components of the intracardiac RAS has been detected in the pressure-overloaded myocardium.5 7 8 Thus, an increased amount of tissue Ang II may exist specifically in the region in which an increased IGF-I synthesis occurs, suggesting Ang II as a possible stimulus for IGF-I gene expression in the pressure-overloaded myocardium.
In conclusion, the present study demonstrates that IGF-I, GH-R, and IGF–I-R gene expression increase in the pressure-overloaded LV of 2K1C hypertensive rats, suggesting a role for the GH/IGF-I axis in the development of cardiac hypertrophy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The present study was supported by grants from the Swedish Medical Research Council (450, 9047, 11133, 2265), Kabi Pharmacia (Stockholm), the Göteborg Medical Society, the Swedish Medical Society, the Swedish Society for Medical Research, the Lundberg Foundation, the Wiberg Foundation, and the Novo Nordisk Foundation. The excellent technical assistance of Gunnel Andersson is appreciated.
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References |
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