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(Hypertension. 2000;35:19.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Inhibitory Regulation of Hypertrophy by Endogenous Atrial Natriuretic Peptide in Cultured Cardiac Myocytes
From the Division of Hypertension, Department of Medicine (T.H., S.T.), and Research Institute (T.N., F.Y., H.M., K.K.), National Cardiovascular Center, Suita, Osaka, Japan.
Correspondence to Takeshi Horio, MD, Division of Hypertension, Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail thorio{at}jsc.ri.ncvc.go.jp
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Abstract |
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Abstract—Atrial natriuretic peptide (ANP) may function as an endogenous regulator of cardiac hypertrophy, because the natriuretic peptide receptor has been found in the heart and because mice lacking its receptor have been shown to have a markedly elevated ventricular mass. We examined the role of endogenous ANP in cardiac hypertrophy in vitro. The effects of the blockade of endogenous ANP by its receptor antagonist, HS-142–1, on cell hypertrophy were investigated with the use of cultured neonatal rat ventricular myocytes. HS-142–1 increased the basal and phenylephrine (PE, 10-5 mol/L)–stimulated protein syntheses in a concentration-dependent manner (1 to 300 µg/mL). A significant increase in the cell size of myocytes was also induced by this antagonist. In addition, the expression levels of skeletal
-actin, ß-myosin heavy chain,
and ANP genes, markers of hypertrophy, were partially
elevated by treatment with HS-142–1 (100 µg/mL) under nonstimulated
or PE-stimulated conditions. A cGMP-specific phosphodiesterase
inhibitor, zaprinast (5x10-4 mol/L), and a
cGMP analogue (10-4 mol/L) suppressed the basal and
PE-stimulated protein syntheses. Our observations suggest that
endogenous ANP inhibits cardiac myocyte
hypertrophy under basal and PE-stimulated conditions,
probably through a cGMP-dependent process. ANP may play a role as an
autocrine factor in the regulation of cardiac myocyte growth.
Key Words: hypertrophy • atrial natriuretic peptide • autocrine-paracrine • myocytes
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Introduction |
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Atrial natriuretic peptide (ANP) is a cardiac hormone that has an important role in the regulation of body fluid homeostasis and systemic blood pressure.1 2 Once in the circulation, ANP binds to its specific receptor, mainly in the vascular tissue, kidney, and adrenal gland, and increases cellular cGMP levels.3 The cGMP production induces vasodilatation, natriuresis, and diuresis.
Subsequent studies have revealed the existence of natriuretic peptide receptors in cardiac cells.4 5 Therefore, apart from acting as a circulating hormone, ANP may have some function as an autocrine and/or paracrine factor. However, the local actions of ANP on the heart itself have not been fully elucidated. Oliver et al6 recently demonstrated with the use of knockout mouse models that the complete absence of one subtype of natriuretic peptide receptors causes marked cardiac hypertrophy, suggesting the possibility that endogenous ANP suppressively regulates the development of cardiac myocyte hypertrophy. With regard to the direct effect of ANP on cardiac hypertrophy, only one study7 reported that exogenous ANP inhibits cardiac myocyte hypertrophy in the limited conditions. Therefore, we conducted the present study to examine the direct effect of endogenous ANP on cell hypertrophy in cultured ventricular myocytes of neonatal rats. We used a specific antagonist for natriuretic peptide receptors, HS-142–1, which competitively and selectively inhibits ANP binding to its biological (guanylyl cyclase [GC]-containing) receptor.8 Several studies have used this antagonist to examine the roles of endogenous ANP in vivo and in vitro.9 10 11 12 We also investigated whether endogenous ANP influences the expression of fetal-type contractile protein genes in addition to the protein synthesis in cultured cardiac myocytes. The participation of cellular cGMP in the effect of ANP on protein synthesis was also examined.
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Methods |
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Cell Cultures
Primary cultures of neonatal ventricular myocytes were prepared as described previously.13 Briefly, apical halves of cardiac ventricles from 1- to 2-day-old Wistar rats were separated, minced, and dispersed with 0.1% collagenase type II (Worthington Biochemical Corp). To segregate myocytes from nonmyocytes, a discontinuous gradient of Percoll (Sigma Chemical Co) was prepared. After centrifugation, the upper layer consisted of a mixed population of nonmyocyte cell types, and the lower layer consisted almost exclusively of cardiac myocytes. After the myocytes were incubated twice on uncoated 10-cm culture dishes for 30 minutes to remove any remaining nonmyocytes, the nonattached viable cells were plated on gelatin-coated 24-well culture plates or 10-cm culture dishes and then cultured in DMEM (Life Technologies) supplemented with 10% FCS (Life Technologies). After a 24-hour incubation in DMEM with FCS, the culture medium was changed to serum-free DMEM, and all experiments were performed 24 hours later. This purification procedure has well been established,14 15 and in fact, >95% of the cells we obtained by this method were cardiomyocytes.
Protein Synthesis and Cell Size Measurement
The effect of various agents on the protein synthesis in
cultured cardiac myocytes was evaluated by the incorporation of
[14C]phenylalanine
(14C-Phe) into cells, according to the method
described by Simpson16 with some modifications. Myocytes
were plated on 24-well plates mainly at a density of
6x104 cells/cm2. Several
experiments were performed at a density of
1.5x104 cells/cm2. After
the preconditioning period, HS-142–1 (a gift from Kyowa Hakko Kogyo,
Tokyo, Japan), phenylephrine (PE, Research Biochemicals,
Inc), endothelin-1 (ET, Peptide Institute), FCS, zaprinast (Biomol
Research Laboratories), 3-isobutyl-1-methylxanthine (IBMX, Nacalai
Tesque), 8-bromo-cGMP (Sigma), 8-bromo-cAMP (Sigma), and/or rat ANP
(Peptide Institute) were added, and 0.3 µCi of
14C-Phe was also added. After the cells were
incubated for 24 hours, the radioactivity of aliquots of the
trichloroacetic acid–insoluble material was determined by a liquid
scintillation counter.
For cell size measurement, 2 or 3 fields in phase-contrast pictures of cultured cardiac myocytes were randomly chosen and photographed, and 50 individual cell surface areas were measured by planimetry.
Northern Blot Analysis
After a 24-hour incubation with treatment of HS-142–1 and/or
PE, the cultured myocytes were submitted for RNA extraction. Total RNA
was extracted from cultured cells with TRIzol Reagent (Life
Technologies). Northern blot analyses were performed with
oligonucleotide probes for rat skeletal -actin mRNA,
ß-myosin heavy chain (ß-MHC) mRNA, and 18S ribosomal RNA and with a
cDNA probe for rat ANP mRNA, according to the method previously
reported.13 17 18
Measurement of Cellular cGMP
After preincubation, myocytes grown in 24-well plates were
treated for 10 minutes with various concentrations of rat ANP, rat
brain natriuretic peptide (BNP, Peptide Institute), and/or
HS-142–1 in the presence of 5x10-4 mol/L IBMX,
as described previously.19 The reaction was stopped by
rapid aspiration of the medium and the addition of ice-cold 70%
ethanol. After each ethanol sample was evaporated by a centrifugal
evaporator, the dry residue was dissolved in an assay buffer. The cGMP
levels were determined by a radioimmunoassay performed with a cGMP
assay kit (Yamasa Shoyu Co), as previously reported.20
Measurement of Immunoreactive ANP and BNP
After cardiac myocytes were treated with HS-142–1 and/or PE for
24 hours, the culture medium was aspirated and stored at -80°C. The
radioimmunoassay for rat ANP and BNP was performed as previously
reported.21
Statistical Analysis
Unpaired t test was used for comparison between the 2
groups. The significance of differences among >3 groups was evaluated
by an unpaired ANOVA, and probability values were calculated by the
Fisher method. A value of P<0.05 was accepted as
statistically significant.
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Results |
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To investigate the secretion levels of ANP and BNP from cultured neonatal rat ventricular myocytes, we examined the immunoreactive (ir)-ANP and ir-BNP concentrations in the medium of cells cultured without FCS. As shown in Table 1, the basal releases of ir-ANP and ir-BNP from myocytes for 24 hours were
10 pmol and 1 pmol per
105 cells, respectively. PE
(10-5 mol/L), ET (10-7
mol/L), and 5% FCS stimulated the secretions of ir-ANP and ir-BNP from
cardiac myocytes. Both the basal and stimulated levels of ir-ANP and
ir-BNP in the medium were significantly increased by HS-142–1 (100
µg/mL).
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The cellular cGMP levels in cultured myocytes were increased
dose-dependently after treatment with 10-9 to
10-6 mol/L ANP (Figure 1A). BNP as well as ANP increased the
cellular cGMP levels, and the effect of BNP on cGMP production
was almost equivalent to that of ANP (data not shown). HS-142–1
decreased the basal level of cGMP and also inhibited the elevation of
cellular cGMP stimulated by 10-8 mol/L ANP
(Figure 1B and 1C). This inhibition by HS-142–1 of the
ANP-induced cGMP production was concentration dependent and
almost complete at doses 
100 µg/mL.
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HS-142–1 elevated the basal level of 14C-Phe incorporation into myocytes at doses of 30 to 300 µg/mL (maximal increase 42%) (Figure 2A). The 14C-Phe incorporation was increased by stimulation with 10-5 mol/L PE, and the PE-induced incorporation of 14C-Phe was further increased by HS-142–1 in a concentration-dependent manner (maximal increase 73%). The increase in protein synthesis by HS-142–1 (100 µg/mL) was also observed under ET- or FCS-stimulated conditions (Table 2). In addition, HS-142–1 induced the significant increase in the cell surface area of myocytes under both nonstimulated and PE-stimulated conditions, in proportion to the increase in protein synthesis (Figure 2B).
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) and PE (10-5 mol/L)–stimulated (•) conditions.
Values are mean±SE of 8 measurements. B, Effect of HS-142–1 (100
µg/mL) on the cell size of cultured cardiac myocytes under
nonstimulated (open bars) and PE (10-5 mol/L)–stimulated
(solid bars) conditions. Values are mean±SE of 50 measurements.
*P<0.05 and **P<0.01 vs control;
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The expression level of skeletal -actin mRNA in cardiac myocytes
treated with HS-142–1 was significantly higher than that of the
controls (Figure 3B). PE elevated the
skeletal -actin gene expression, but a further increase in its level
was not obtained by the addition of HS-142–1. The expression of
ß-MHC mRNA was elevated by HS-142–1 under PE-treated conditions
(Figure 3C). The mRNA level of ANP was increased by HS-142–1
under both nonstimulated and PE-stimulated conditions (Figure 3D).
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To elucidate whether the inhibitory effect of
endogenous ANP on myocyte hypertrophy is
causally linked to the increase in cellular cGMP, we examined the
effects of 2 phosphodiesterase inhibitors on protein
synthesis in cultured cardiac myocytes. A cGMP-specific
phosphodiesterase inhibitor, zaprinast, and a nonspecific
inhibitor, IBMX, elevated the cellular cGMP levels at doses
10-4 mol/L, in the presence of
10-8 mol/L ANP (data not shown). Both zaprinast
(5x10-4 mol/L) and IBMX
(5x10-4 mol/L) significantly decreased the
14C-Phe incorporation into cells (Figure 4A). The extent of the decrease in
14C-Phe incorporation by these
inhibitors was larger in PE-stimulated myocytes than in
nontreated cells. The effect of exogenous cGMP on protein synthesis was
also examined. A cGMP analogue, 8-bromo-cGMP
(10-4 mol/L), diminished the basal and
PE-stimulated 14C-Phe uptake into cells (Figure 4B). In contrast, 8-bromo-cAMP (10-3
mol/L) slightly but significantly elevated the uptake of
14C-Phe only in PE-stimulated cells.
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As shown in Figure 5A, exogenous ANP (10-7 to 10-6 mol/L) did not inhibit the 14C-Phe incorporation into cultured myocytes incubated at a density of 6x104 cells/cm2, which is the cell density used in other experiments in the present study. However, the increased uptake of 14C-Phe by treatment with 50 µg/mL HS-142–1 was suppressed significantly by 10-6 mol/L ANP (Figure 5C). When cultured cells were prepared at a low density (1.5x104 cells/cm2), the 14C-Phe incorporation levels under both basal and PE-stimulated conditions were decreased by 10-6 mol/L ANP (Figure 5B).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study has demonstrated for the first time that the blockade of endogenous ANP induces the hypertrophy of cultured neonatal rat ventricular myocytes. HS-142–1, a natriuretic peptide receptor antagonist, clearly increased the protein synthesis and cell size of cardiac myocytes under basal and PE-stimulated conditions. In the presence of an excessive dose of exogenous ANP, however, HS-142–1 failed to increase the protein synthesis (Figure 5C). This result indicates that the effect of HS-142–1 observed in the present study is not due to nonspecific stimulation but really due to the competitive and specific inhibition of ANP binding.
Three receptor subtypes for natriuretic peptides are presently known.22 23 Two of these receptors have GC activity and are called GC-A and GC-B.3 22 Although HS-142–1 is a competitive antagonist for both GC-A and GC-B,8 the observed increase in protein synthesis by this antagonist in the present study appears to be mainly through a GC-A blockade, because rat ventricular myocytes have been reported to produce predominantly GC-A.5 Among the 3 members of the natriuretic peptide family (ANP, BNP, and C-type natriuretic peptide), both BNP and ANP combine with GC-A.3 22 In fact, we confirmed that BNP has an effect that is almost equivalent to the effect of ANP on the production of cellular cGMP in cultured cardiac myocytes. However, the secretion level of ANP in neonatal rat ventricular myocytes was much higher than that of BNP. Therefore, the induction of cell hypertrophy by HS-142–1 obtained in the present study may be due mainly to a blockade of endogenous ANP.
Oliver et al6 recently reported that hypertension and
cardiac hypertrophy were found in GC-A knockout mice; these
mice lacking GC-A had elevated blood pressure and hearts exhibiting
marked hypertrophy with interstitial fibrosis.
Mice homozygous for disruption of the pro-ANP gene have no circulating
or tissue ANP, and they exhibit increased heart weight and blood
pressure when maintained on intermediate salt diets.24
Transgenic mice overexpressing ANP have a low heart weight under
normoxic conditions and a blunted right ventricular
hypertrophy response to hypoxia-induced
pulmonary hypertension.25 These observations
suggest that ANP may be closely associated with the progression of
myocardial hypertrophy. However, the issue of whether the
influence of ANP on cardiac hypertrophy is a direct effect
of its peptide or secondary to the change of blood pressure levels was
not resolved by these studies using knockout or transgenic mice. With
regard to the direct effect of ANP on cardiac hypertrophy,
a very recent report (Calderone et al7 ) has shown that
exogenous ANP and cGMP inhibit the protein synthesis of neonatal
cardiomyocytes under limited conditions, that is, in
norepinephrine-stimulated cells cultured at a low density
(1 to 2x104 cells/cm2).
The study of Calderone et al and another study26 showed
that the inhibitory effect of cGMP was absent in cells
cultured at a high density (1x105
cells/cm2). Therefore, the study of Calderone et
al could not determine whether endogenous ANP may have an
inhibitory effect on myocyte hypertrophy. Our
present study demonstrates that endogenous ANP has a
direct action on myocyte hypertrophy, independent of the
hemodynamic change, in the cells cultured even at a
high density and, furthermore, under both PE-stimulated and
nonstimulated (basal) conditions. In addition, the present results
have shown that myocyte hypertrophy produced by the
blockade of endogenous ANP by HS-142–1 is partially
accompanied by increases in the expression of skeletal -actin,
ß-MHC, and ANP genes, which are genetic markers for
cardiomyocyte hypertrophy. These results
indicate that endogenous ANP may influence the growth of
neonatal cardiac myocytes with qualitative changes.
Regarding the mechanism of inhibitory effect of ANP on cellular hypertrophy, we have obtained some evidence of a causal relation between cGMP production and inhibition of cell hypertrophy by ANP. ANP markedly increased the cGMP levels in cells, and a cGMP-specific phosphodiesterase inhibitor and a cGMP analogue suppressed the basal and PE-stimulated protein syntheses. These results suggest that endogenous ANP and exogenous ANP inhibit the protein synthesis in cardiac myocytes, probably through a cGMP-dependent process. We cannot deny the possibility that the increase in the cellular cGMP level after treatment with a cGMP-specific phosphodiesterase inhibitor may be derived not only from endogenous ANP but also from endogenous nitric oxide. However, the cGMP production in the presence of a considerable amount of ANP is thought to be derived mostly from ANP, because the cellular cGMP production in the presence of 10-8 mol/L ANP was inhibited almost completely by HS-142–1.
In the present study, both the increase in protein synthesis by HS-142–1 and its decrease by phosphodiesterase inhibitors were greater in PE-stimulated myocytes than in nonstimulated cells. These data indicate that the effects of endogenous ANP and cGMP are probably accelerated by the stimulation with PE. Some studies have shown that ANP also inhibits the catecholamine-induced and growth factor–induced DNA synthesis of cultured rat cardiac fibroblasts.4 7 27 Although ANP expression is minimal in normal adult ventricular myocardium, cardiac overload and hypertrophy induce ANP production in the ventricles.28 29 30 31 In human failing or hypertrophied hearts, the expression of ANP is remarkably induced, and considerable levels of its peptide are detected in the ventricles.28 29 30 These findings lead to the possibility that endogenous ANP plays a role as an autocrine and/or paracrine inhibitory regulator against excessive cardiac cell growth in some pathological states, such as heart failure and cardiac hypertrophy. However, the present study was performed with the use of cultured neonatal, not adult, cardiac myocytes of rats, as in many other studies. Alternatively, it is possible that ANP regulates the myocardial growth during development, in view of the fact that fetal and neonatal myocardium express the ANP gene and peptide even in the normal state.13 28 32 Further investigations are necessary to clarify the physiological and pathophysiological effects of endogenous ANP on cardiac myocytes.
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Acknowledgments |
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This study was supported in part by Special Coordination Funds for Promoting Science and Technology (Encouragement System of COE) from the Science and Technology Agency of Japan; grants from the Ministry of Health and Welfare, the Human Science Foundation of Japan; Scientific Research Grant-in-Aid 09670776 from the Ministry of Education, Science and Culture of Japan; grants from Japan Cardiovascular Research Foundation; a grant provided by the Ichiro Kanehara Foundation; a grant provided by the Motida Memorial Foundation for Medical and Pharmaceutical Research; and a grant provided by the Yamanouchi Foundation for Research on Metabolic Disorders. We thank Yoko Saito for her technical assistance.
Received April 13, 1999; first decision May 6, 1999; accepted August 23, 1999.
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E. Takimoto and D. A. Kass Role of Oxidative Stress in Cardiac Hypertrophy and Remodeling Hypertension, February 1, 2007; 49(2): 241 - 248. [Full Text] [PDF]
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M. D. Jarvis, M. T. Rademaker, L. J. Ellmers, M. J. Currie, J. L. McKenzie, B. R. Palmer, C. M. Frampton, A. M. Richards, and V. A. Cameron Comparison of infarct-derived and control ovine cardiac myofibroblasts in culture: response to cytokines and natriuretic peptide receptor expression profiles. Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1952 - H1958. [Abstract] [Full Text] [PDF]
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A. Laskowski, O. L. Woodman, A. H. Cao, G. R. Drummond, T. Marshall, D. M. Kaye, and R. H. Ritchie Antioxidant actions contribute to the antihypertrophic effects of atrial natriuretic peptide in neonatal rat cardiomyocytes Cardiovasc Res, October 1, 2006; 72(1): 112 - 123. [Abstract] [Full Text] [PDF]
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S. Rubattu, G. Bigatti, A. Evangelista, C. Lanzani, R. Stanzione, L. Zagato, P. Manunta, S. Marchitti, V. Venturelli, G. Bianchi, et al. Association of Atrial Natriuretic Peptide and Type A Natriuretic Peptide Receptor Gene Polymorphisms With Left Ventricular Mass in Human Essential Hypertension J. Am. Coll. Cardiol., August 1, 2006; 48(3): 499 - 505. [Abstract] [Full Text] [PDF]
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G. Singh, R. E. Kuc, J. J. Maguire, M. Fidock, and A. P. Davenport Novel Snake Venom Ligand Dendroaspis Natriuretic Peptide Is Selective for Natriuretic Peptide Receptor-A in Human Heart: Downregulation of Natriuretic Peptide Receptor-A in Heart Failure Circ. Res., July 21, 2006; 99(2): 183 - 190. [Abstract] [Full Text] [PDF]
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T. Nishikimi, N. Maeda, and H. Matsuoka The role of natriuretic peptides in cardioprotection Cardiovasc Res, February 1, 2006; 69(2): 318 - 328. [Abstract] [Full Text] [PDF]
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J. B. Patel, M. L. Valencik, A. M. Pritchett, J. C. Burnett Jr., J. A. McDonald, and M. M. Redfield Cardiac-specific attenuation of natriuretic peptide A receptor activity accentuates adverse cardiac remodeling and mortality in response to pressure overload Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H777 - H784. [Abstract] [Full Text] [PDF]
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M. Nakanishi, Y. Saito, I. Kishimoto, M. Harada, K. Kuwahara, N. Takahashi, R. Kawakami, Y. Nakagawa, K. Tanimoto, S. Yasuno, et al. Role of Natriuretic Peptide Receptor Guanylyl Cyclase-A in Myocardial Infarction Evaluated Using Genetically Engineered Mice Hypertension, August 1, 2005; 46(2): 441 - 447. [Abstract] [Full Text] [PDF]
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T. Nishikimi, J. R. Hagaman, N. Takahashi, H.-S. Kim, H. Matsuoka, O. Smithies, and N. Maeda Increased susceptibility to heart failure in response to volume overload in mice lacking natriuretic peptide receptor-A gene Cardiovasc Res, April 1, 2005; 66(1): 94 - 103. [Abstract] [Full Text] [PDF]
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J. C. Y. Chan, O. Knudson, F. Wu, J. Morser, W. P. Dole, and Q. Wu Hypertension in mice lacking the proatrial natriuretic peptide convertase corin PNAS, January 18, 2005; 102(3): 785 - 790. [Abstract] [Full Text] [PDF]
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