(Circulation. 1997;95:2677-2683.)
© 1997 American Heart Association, Inc.
Articles |
Load-Induced Growth Responses in Isolated Adult Rat Hearts
Role of the AT1 Receptor
From the Charles A. Dana Research Institute and Harvard-Thorndike Laboratory of Beth Israel Deaconess Medical Center (Cardiovascular Division) and Harvard Medical School, Boston, Mass.
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Abstract |
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Background Stimulation of the angiotensin II type 1 (AT1) receptor by angiotensin II appears to be mandatory for the acute load-induced hypertrophic response of cultured neonatal rat cardiocytes, but its role in the adult heart is controversial. We tested the hypothesis that AT1 receptor blockade will inhibit the acute induction of proto-oncogenes and protein synthesis by the elevation of systolic wall stress in isolated beating adult rat hearts.
Methods and Results Using the established isovolumic perfused heart preparation under constant coronary flow, we found that an increment in left ventricular balloon volume generated an increase in systolic wall stress. The induction of left ventricular c-fos and c-myc mRNA (Northern blotting) was assessed in hearts subjected to increased systolic load without AT1 blockade (No AT1, n=11) and with AT1 blockade (AT1, n=11, losartan 40 mg·kg-1·d-1x5 days followed by 10-5 mol/L infusion during perfusion). Flaccid hearts (no left ventricular balloon) served as controls (C, n=9). The stimulation of new protein synthesis in response to increased systolic load was measured by incorporation of [3H]phenylalanine into cardiac proteins. Elevation of systolic load was associated with a twofold (P<.05) increase in c-fos and c-myc mRNA levels that was not blocked by losartan. The rate of [3H]phenylalanine incorporation into cardiac proteins was increased 2.7-fold (P<.01) in hearts subjected to increased systolic load compared with control hearts. However, AT1 receptor blockade with losartan did not prevent the stimulation of [3H]phenylalanine incorporation (881±97 versus 923±82 nmol·g protein-1·h-1, P=NS).
Conclusions In contrast with immature myocytes subjected to stretch, the acute growth responses induced by systolic pressure overload in adult rat hearts do not depend on AT1 receptor activation.
Key Words: angiotensin • RNA • myocardium • hypertrophy
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Introduction |
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Both neurohormonal factors such as angiotensin II and cardiac load are important mechanisms that stimulate the growth of the heart.1 2 Angiotensin II induces hypertrophy in neonatal myocytes that is mediated by the angiotensin II type 1 (AT1) receptor and activation of protein kinase C.3 4 Similarly, using isolated perfused adult rat hearts, we have shown that angiotensin II stimulates cardiac protein synthesis independent of load and that this response depends on translocation of protein kinase C and is blocked by the specific AT1 receptor antagonist losartan.5 6
The signals that transduce changes in cardiac load to initiate cardiac hypertrophy in the immature and adult heart are not yet clearly identified. In neonatal cultured rat myocytes, passive stretch has been used as a tool to investigate cellular mechanisms of myocyte hypertrophy.7 8 In cultured neonatal rat myocytes, passive stretch stimulates the immediate growth response of the induction of proto-oncogenes and new protein synthesis that is mediated by the autocrine release of angiotensin II and blocked by inhibition of the AT1 receptor with the AT1 receptor antagonist losartan.9 Thus, in immature cultured myocytes, AT1 receptor activation appears to be mandatory for the immediate load-induced growth response. In adult perfused rat hearts, we have demonstrated that an acute increase in systolic left ventricular wall stress distinct from passive diastolic wall stretch per se also causes this acute growth response of the induction of proto-oncogenes, including c-fos and c-myc,10 and new cardiac protein synthesis measured by the incorporation of [3H]phenylalanine.5 6 Whether these effects of systolic load on cardiac proto-oncogene induction and protein synthesis in the adult heart are mediated by AT1 receptor activation, however, is not known. Thus, in the present study, we tested the hypothesis that the induction of proto-oncogene expression and cardiac protein synthesis by systolic load in normal adult isolated hearts could be blocked by the AT1 receptor antagonist losartan.
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Methods |
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Perfusion of Isolated Hearts
Male Wistar rats (350 to 450 g) were obtained from Charles River Breeding Laboratories (Wilmington, Mass). Animals were fed standard rat chow (Purina) and water ad libitum and housed in a virus- and antigen-free facility. Perfusion techniques using a modified Langendorff apparatus in isolated rat hearts in our laboratory have been described previously.10 11 12 The perfusate consisted of modified Krebs-Henseleit buffer (in mmol/L: NaCl 118, KCl 4.7, CaCl2 2.0, KH2PO4 1.2, MgSO4 1.2, NaHCO3 25, glucose 5.5, EDTA 0.4, and lactate 1.0). For measurements of protein synthesis, the buffer also contained 0.05% albumin and a mixture of amino acids in the following concentrations (µmol/L): aspartic acid 38, asparagine 64, glutamic acid 207, glutamine 656, glycine 328, alanine 559, valine 226, leucine 184, isoleucine 99, serine 285, threonine 371, methionine 57, proline 246, phenylalanine 400, tyrosine 119, tryptophan 84, histidine 77, lysine 532, cysteine 273, and arginine 157.13 14 The perfusate was equilibrated with a 5% CO2/95% O2 gas mixture. All solutions also contained the
1-blocker prazosin (10-7 mol/L)
to prevent any indirect stimulation of protein synthesis via activation
of the postsynaptic sympathetic nervous system. The left ventricle was
decompressed by insertion of a short apical drain to vent thebesian
flow. The temperature of the hearts was kept constant at 35°C. Before
hearts were subjected to the experimental protocol, the cardiac
performance was allowed to stabilize, and the perfusion
pressure was adjusted to 80 mm Hg.
Experimental Protocols in Isolated Hearts
Effects of AT1 Blockade on Proto-oncogene
Expression
The beating hearts were subjected to an acute elevation of
isovolumic systolic wall stress by distension of a fluid-filled
balloon in the left ventricular chamber as previously
described.5 6 10 The hearts were initially perfused for 10
to 15 minutes with flaccid balloons and no left ventricular
pressure generation. The left ventricular balloon was then
distended such that the hearts developed a left ventricular
systolic pressure of 
120 mm Hg, corresponding to an
elevated systolic wall stress of 550x103
dynes/cm2 for a total of 60 minutes as previously
described.5 6 10 We have previously demonstrated that
passive stretch of the left ventricle with distension of the balloon
alone does not affect proto-oncogene induction.10 Three
groups were studied. One group of hearts (No AT1, n=11) was
not subjected to AT1 receptor blockade. A second group of
hearts (AT1, n=11) were obtained from rats that received
the AT1 receptor antagonist losartan
for 5 days (40
mg·kg-1·d-1)
followed by the continuous infusion of 10-5
mol/L losartan during the perfusion experiments. We found in
pilot studies that this losartan dosing protocol compared with
no drug (n=5 per group) completely blocked changes in coronary
perfusion pressure (
2.5±0.3 versus 23±2.6 mm Hg,
P<.05) due to infusion of 5x10-8
mol/L angiotensin II in isolated hearts. A third group of
flaccid hearts with no balloon (C, n=9) received no drug and served as
controls with minimal systolic load.10 At the end
of the perfusion protocol, the left ventricles were freeze-clamped in
liquid nitrogen and stored at -70°C for RNA measurements.
Effects of AT1 Blockade on Amino Acid Incorporation in
Isolated Perfused Hearts
Hearts were subjected to elevated systolic wall stress
alone (No AT1, n=7), elevated systolic wall stress
with AT1 blockade with losartan as described above
(AT1, n=8), or no systolic load (C, n=8) for 60
minutes with the modified Krebs-Henseleit buffer containing a mixture
of amino acids as described above. After 60 minutes, the left
ventricular balloon was emptied, and hearts were perfused
for another 120 minutes with the same buffer plus 0.5 mCi/L
radiolabeled [3H]phenylalanine. Thus, the hearts were
allowed to incorporate radiolabeled phenylalanine into newly
synthesized proteins for 2 hours. Unlabeled phenylalanine, present
in a defined concentration in the buffer, was used for calculation of
the incorporation of phenylalanine into cardiac proteins on a molar
basis.5 6 12 13 Phenylalanine incorporation was assumed to
be linear over the 2-hour period of incorporation, and data are
expressed as mol phenylalanine·g
protein-1·h-1.13 14
Biochemical Analyses
Protein Synthesis
After the perfusion protocols, the atria and great vessels were
quickly removed. Left and right ventricles were blotted dry, weighed,
and freeze-clamped in liquid nitrogen. For measurement of protein
synthesis, the methods of Morgan et al14 with
modifications by Kent et al15 were used as previously
reported from our laboratory.5 6 An aliquot (100 mg) was
minced and homogenized in 1 mL ice-cold 5% perchloric acid
to denature proteins and to remove unincorporated
[3H]phenylalanine. After centrifugation,
the pellet was washed with 5% perchlorate, resuspended, and heated to
80°C to remove RNA-bound [3H]phenylalanine. After
centrifugation, the pellet was washed with 5%
perchlorate and then resuspended in 0.2N NaOH. An aliquot (50
µL) of this solution was used for protein assay, and a second aliquot
(500 µL) was used for liquid scintillation counting. The net protein
synthesis by the left ventricle during the 120 minutes of
perfusion with [3H]phenylalanine was calculated as
follows: phenylalanine incorporation (mol·g
protein-1·h-1)=phenylalanine
(dpm·g
protein-1·h-1)/perfusate
phenylalanine specific activity (dpm/mol).
RNA Measurements
RNA extraction, standard Northern blot analysis, and
hybridization conditions have been described before in
detail.5 6 10 RNA was extracted by the cesium/guanidine
thiocyanate method5 6 10 and was quantified by absorbance
at 260 nm. Total cellular RNA (20 µg) from individual ventricles was
size-fractionated by electrophoresis on a 1.0% agarose-formaldehyde
gel and transferred to nylon membrane (Gene Screen, Dupont-NEN Research
Products) by pressure transfer (Posiblot Pressure Blotter,
Stratagene Inc). Membranes were prehybridized at 68°C in Quick-Hyb
Solution (Stratagene) and hybridized in the same solution containing
100 µg/mL salmon sperm DNA and the specific 32P-labeled
cDNA probes. After hybridization, the blots were washed in varying
concentrations of SSC and SDS and then exposed to Kodak MR film with an
intensifying screen for 0.25 to 7 days at -80°C. The relative
amounts of each mRNA were determined by laser densitometry, and
densitometric scores of c-fos and c-myc were
normalized to that of GAPDH as previously described.16 The
32P-labeled cDNA probes used in this study included a
2.1-kb fragment of the cDNA encoding rat c-fos, the cDNA
clone pG2 myc5,8 and a 1.3-kb Pst I
fragment of the cDNA encoding rat GAPDH.17
Effects of ACE Inhibition on Proto-oncogene Expression
To exclude a contribution of active formation of
angiotensin II on cardiac angiotensin II
receptor subtypes other than the AT1 receptor subtype, we
also examined the effects of ACE inhibition with enalapril on the load
induction of proto-oncogenes and (in separate experiments) of
phenylalanine incorporation. Three groups were studied. One group of
hearts (No ACE inhibitor, n=5) received no enalapril
treatment during the wall stress perfusion protocol. A second group of
hearts (ACE inhibitor, n=5) received continuous infusion of
4x10-6 mol/L enalapril into the isolated
hearts for 15 minutes before and during the systolic wall
stress perfusion protocol. We have recently shown that this dosing
regimen blocks the intracardiac conversion of angiotensin I
to II in isolated perfused rat hearts.12 A third group of
flaccid hearts with no balloon (C, n=5) received no drug and served as
controls with no systolic load. Hearts were subjected to the
systolic wall stress perfusion protocol and subsequent
quantification of cardiac proto-oncogene mRNA levels. In separate
cohorts of hearts (n=5 to 8 per group), phenylalanine incorporation was
measured as described above.
Statistical Analysis
All data are expressed as mean±SEM. Phenylalanine incorporation
or proto-oncogene/GAPDH mRNA ratios were compared by Student's
unpaired t tests. ANOVA and Fisher's protected least
significant difference test for post hoc analyses were used for
comparisons in the case of three or more comparisons between groups.
Significance was accepted at a value of P<.05.
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Results |
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Hemodynamics
To address potential confounding effects of hemodynamics distinct from the elevation of systolic load on the induction of proto-oncogene expression and protein synthesis,18 19 coronary flow was similar and coronary perfusion pressure was adjusted to a stable level of 80 mm Hg in all hearts. Systolic wall stress was elevated by inflating the left ventricular balloon to achieve a left ventricular systolic pressure of
120 mm Hg for 60 minutes.10 Hearts were perfused
in the absence (no AT1 group) and presence of
AT1 receptor blockade with losartan
(AT1 group). A third group of hearts with flaccid left
ventricles served as controls. There was no significant difference in
body weight or left ventricular weight among the three
groups (Table 1
). Table 1 shows the
hemodynamic data for the protocol that examined the
effects of AT1 receptor blockade and Table 2
shows the hemodynamic data for the protocol that
examined the effects of ACE inhibition on proto-oncogene expression and
phenylalanine incorporation. In the groups subjected to increased
systolic wall stress, left ventricular
systolic pressure per gram, left ventricular
end-diastolic pressure, coronary flow, and heart
rate were similar.
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Effects of AT1 Blockade on Proto-oncogene
Expression
The elevation of systolic wall stress for 1 hour was
associated with a 2.1-fold increase in left ventricular
c-fos mRNA levels and a 2.0-fold increase in
c-myc levels relative to the control hearts
(P<.05), corroborating our previous observations (Fig 1). As shown in Fig 1, AT1 receptor blockade
with losartan did not inhibit left ventricular
c-fos or c-myc induction by systolic load
(P=NS).
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Effects of AT1 Blockade on New Cardiac Protein
Synthesis
In the presence of elevated systolic wall stress alone,
phenylalanine incorporation was 343±40 nmol·g
protein-1·h-1
(2.7-fold increase compared with control group, P<.05),
consistent with our previous findings.5 6 As shown
in Fig 2, in hearts subjected to an increase in
systolic wall stress in the presence of losartan,
phenylalanine incorporation was not blocked in comparison with hearts
subjected to a similar increase in systolic load in the absence
of drug (881±97 versus 923±82 nmol·g
protein-1·h-1,
P=NS).
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Effects of ACE Inhibition on Proto-oncogene Expression
To exclude a contribution of active formation of
angiotensin II on cardiac angiotensin II
receptor subtypes other than the AT1 receptor subtype, the
effects of ACE inhibition with enalapril on the load induction of
proto-oncogenes and phenylalanine incorporation were also examined. As
shown in Fig 3, ACE inhibition with enalapril did not
prevent the induction of c-fos and c-myc in
response to systolic load. In addition, Fig 4
illustrates that phenylalanine incorporation was not blocked by ACE
inhibition in comparison with hearts subjected to a similar increase in
systolic load in the absence of drug (896±59 versus 747±46
nmol·g
protein-1·h-1,
P=NS).
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Discussion |
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The obligate signals that transduce changes in cardiac load to initiate cardiac hypertrophy in intact immature and adult hearts are not yet clearly identified. Banding of the ascending aorta in rats results in systolic pressure overload and the immediate induction of cardiac c-fos, c-jun, and c-myc proto-oncogenes, which is followed by an increase in cardiac protein synthesis and an altered expression of gene isoforms encoding contractile and regulatory proteins.2 16 20 Using adult perfused rat hearts, we have demonstrated that an acute increase in left ventricular systolic wall stress distinct from passive diastolic wall stretch per se also causes this acute growth response of the induction of the proto-oncogenes c-fos, c-myc, and c-jun and new cardiac protein synthesis measured by the incorporation of [3H]phenylalanine.5 6 10
In neonatal cultured rat myocytes, passive stretch and deformation of quiescent cells has been used as a tool to investigate cellular mechanisms of myocyte hypertrophy.7 8 In cultured neonatal rat myocytes, passive stretch also stimulates the immediate growth response of the induction of proto-oncogenes and new protein synthesis.8 Sadoshima et al9 observed that this early growth response appears to be mediated by the autocrine release of angiotensin II and blocked by inhibition of the AT1 receptor with the AT1 receptor antagonist losartan. It is compelling to hypothesize that AT1 receptor activation also mediates the induction of immediate growth responses due to acute pressure overload in the intact adult heart. We have demonstrated the presence of a local cardiac renin-angiotensin system in normal adult rat hearts that is upregulated in the presence of chronic pressure overload hypertrophy.11 12 Recent studies by our group21 and other laboratories22 23 have also shown that in normal rat ventricles and myocytes, angiotensin II receptors are present and are predominantly the AT1 receptor subtype.
Thus, we tested the hypothesis that the induction of proto-oncogene expression and cardiac protein synthesis by systolic load in normal adult perfused hearts could be blocked by the AT1 receptor antagonist losartan. In the present experiment, we corroborated our previous findings that an acute increase in systolic wall stress is followed by the induction of c-fos and c-myc and an increase in new cardiac protein synthesis.5 6 10 To examine the effects of AT1 receptor blockade on this response, rats were chronically treated with the AT1 receptor antagonist losartan for 5 days followed by continuous infusion of the drug during the isolated heart perfusion protocols. This dosing regimen was sufficient to completely block the hemodynamic effects of angiotensin II infusion that we have previously observed in isolated perfused hearts.21 We observed that AT1 receptor blockade with losartan did not block the effects of elevated systolic wall stress on proto-oncogene induction or new cardiac protein synthesis. Thus, in contrast with cultured myocytes subjected to passive stretch, AT1 receptor activation does not appear to be mandatory for the immediate load-induced growth response in normal adult rat hearts.
Several factors may account for this difference in the role of AT1 receptor activation on the stretch-induced early growth response in cultured myocytes versus the effects of systolic load on the intact beating adult heart. First, there may be critical differences between the characteristics of mechanical load that stimulate physiological growth of the immature heart versus pathological systolic pressure overload hypertrophy of the adult heart.24 25 During development, the heart enlarges by eccentric hypertrophy, that is, a predominant increase in left ventricular volume relative to wall thickness, which is postulated to be related to increments in passive diastolic wall stretch imposed by an enlarging circulatory volume. In this regard, passive stretch of cultured neonatal myocytes would appear to be a reasonable surrogate for the loading conditions that stimulate growth of the immature heart in vivo. In the adult heart, in contrast, systolic pressure overload has been identified as the stimulus for concentric pressure overload hypertrophy in humans and animal models with aortic stenosis or hypertension.25 26
In this regard, to distinguish the role of passive diastolic stretch from active systolic force generation, we have demonstrated that passive distension of the left ventricle per se over a range of physiological diastolic volumes did not modify proto-oncogene induction in normal perfused hearts when systolic force generation was prevented by perfusion with 2,3-butanedione monoxime.10 An additional confounding component of load in the intact heart is the contribution of coronary turgor. Kang et al27 recently reported that load-induced c-fos expression in intact hearts was blunted by treatment with an AT1 receptor blocker; in that study, however, interpretation of effects of systolic load was confounded by a marked increase in coronary perfusion pressure and twofold elevation of coronary flow. A strength of the present study is that coronary flow was not perturbed.
In addition, angiotensin II–mediated regulation of proto-oncogenes and protein synthesis may differ in neonatal and adult myocytes in comparison with the intact adult heart. Fetal and neonatal tissues demonstrate a greater abundance of angiotensin II receptors than the adult heart, which rapidly decrease postnatally.22 23 28 Cardiac levels of c-fos and c-myc also diminish rapidly during postnatal life.29 Furthermore, there are also differences in phosphatidyl inositol signaling between isolated cultured adult myocytes and intact adult rat hearts.30 Kent and McDermott31 have reported that load-induced c-fos expression was angiotensin II–dependent in quiescent adult cardiocytes subjected to passive stretch, although accelerated protein synthesis was not. In this regard, we have previously demonstrated that angiotensin II–induced induction of c-fos and activation of protein kinase C translocation is much less pronounced in the intact beating adult heart than in isolated quiescent adult cultured myocytes.5 Thus, the present study extends these lines of evidence that the intracellular signal transduction that mediates both load-induced and angiotensin II–induced protein synthesis may differ in isolated cultured myocytes compared with the intact beating adult heart.
The present study of the immediate growth response induced by systolic load in isolated hearts has several limitations. First, the duration of the experiment in the isolated heart model is insufficient to examine later components of the growth response, including the upregulation of genes that are characteristic of the hypertrophic gene program, such as atrial natriuretic factor and ß-myosin heavy chain,1 2 32 as well as myocyte hypertrophy. Second, the present study did not clarify whether the load-induced stimulation of proto-oncogene induction and protein synthesis is localized to cardiac myocytes or is partly related to other cellular components, such as fibroblasts, that also contain AT1 receptors. In this regard, we have previously demonstrated that the elevation of systolic load in this isolated adult heart model is associated with an increase in fos protein that is localized predominantly to the cardiomyocyte.10 Finally, the relative role of AT1 versus AT2 receptor activation on the immediate growth response to load is not yet clear. Whereas recent studies suggest that AT2 receptor activation suppresses cell growth in vascular smooth muscle33 and endothelial cells34 and promotes apoptosis in fibroblasts,35 it is not known whether AT2 receptor activation suppresses or stimulates growth of the adult myocyte. Our experiments did not exclude the possibility that active intracardiac formation of angiotensin II via ACE, which is the predominant pathway in the rat, could be contributing to activation of receptor subtypes other than the AT1 receptor. Therefore, we also performed experiments to examine the effects of ACE inhibition with enalapril, which showed that ACE inhibition did not prevent the induction of proto-oncogenes or new cardiac protein synthesis. These data exclude a contribution of intracardiac angiotensin II formation acting on receptor subtypes other than the AT1 receptor.
Our observations indicate that AT1 receptor activation does not play a role in the immediate growth responses to increased systolic load, but these findings do not address the potential impact of AT1 receptors during chronic load such as prolonged hypertension in the clinical setting. Although several previous studies,36 37 38 including studies from our laboratory,39 have shown that chronic ACE inhibition can regress hypertrophy even at doses that do not modify systolic load, ACE inhibitors have multiple actions that may chronically modify growth, such as stimulation of kinin–nitric oxide signaling.38 Relevant to the clinical setting, previous studies have shown that AT1 receptor blockade can blunt hypertrophic growth in vivo if drug dosage is sufficient to cause a reduction in blood pressure and left ventricular systolic load.40 41 However, we have shown that chronic AT1 receptor inhibition in aortic-banded rats, in the presence of persistent elevation of left ventricular systolic load, failed to regress left ventricular hypertrophy.42 McDonald et al43 found that AT1 receptor blockade did not attenuate hypertrophic remodeling in the dog after transmyocardial shock injury. Similarly, Koide et al44 reported that AT1 blockade failed to modify pressure overload hypertrophy in cats with pulmonary artery banding. In addition, Hamawaki et al45 reported preliminary findings that knockout of the AT1 receptor did not prevent cardiac hypertrophy in adult transgenic mice subjected to aortic banding. Taken together, these observations suggest that cardiac AT1 receptor activation is not obligate for load-induced hypertrophy in the intact adult heart.
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Acknowledgments |
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This work was supported in part by a grant from the National Heart, Lung, and Blood Institute (HL-39091, Drs Weinberg and Lorell), and by a Konrad-Adenauer Fellowship (C. Thienelt). We thank Tony L. Baptista for his assistance in preparing the manuscript. The study drugs losartan and enalapril were graciously supplied by Merck, Inc.
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Footnotes |
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Reprint requests to Beverly H. Lorell, MD, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215.
Received September 12, 1996; revision received December 23, 1996; accepted January 4, 1997.
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