© 2000 American Heart Association, Inc.
Clinical Research |
Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy
Endothelin-1 System in the Human Failing Heart
Presented in part at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8–11, 1998, and published in abstract form (Circulation. 1998;98[suppl I]:I-768).
From the Clinica Medica Generale e Cardiologia (G.G.N.S., I.C., S.V., R.P., B.B., A.V., X.J., I.B., M.B., P.A.M.), University of Florence; Institute of Thoracic and Cardiovascular Surgery (G.F.L.), University of Siena; and Department of Cardiosurgery (G.S.), University of Cagliari, Italy.
Correspondence to Gian Gastone Neri Serneri, Clinica Medica Generale e Cardiologia, University of Florence, Viale Morgagni 85, 50134 Florence, Italy.
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Abstract |
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Abstract—Only scarce information is available on the activity and modifications of the cardiac endothelin (ET)–1 system in heart failure due to ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. The activity of the ET-1 system was investigated by measuring cardiac ET-1 and big ET-1 formation and quantifying cardiac mRNA for prepro–ET-1 (ppET-1), ET-converting enzyme-1, and ETA and ETB receptors both in myocardium and in isolated myocytes using Northern blot, reverse transcription–polymerase chain reaction, and in situ hybridization in 22 patients with DCM and 20 with ICM who underwent cardiac transplantation and in 7 potential heart transplant donors (nonfailing hearts). Notwithstanding a similar increase of plasma ET-1 in the 2 groups, cardiac ET formation, mRNA levels for ppET-1, and ETA and ETB receptors were higher on both the myocardium and isolated myocytes from ICM than on those from DCM hearts (P<0.001 for all). ppET-1 and ET-converting enzyme-1 mRNAs were expressed on myocytes and endothelial and interstitial cells in ICM, whereas in DCM and nonfailing hearts they were mainly expressed on nonmyocyte cells. In both ICM and DCM, the ETA mRNA signal was expressed on both myocytes and nonmyocyte cells, whereas ETB mRNA was almost exclusively localized on nonmyocyte cells. ETA- and ETB-specific receptor binding was increased on both myocytes and cardiac membranes, showing a positive correlation with left ventricular ejection fraction in ICM (r=0.78 and 0.70) but not in DCM patients. The present results show that human ventricular myocytes express all of the components of the ET-1 system, which is selectively upregulated in ICM patients and appears to be functionally important in the maintenance of cardiac function.
Key Words: endothelin • heart failure • myocytes • receptors • RNA
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Introduction |
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Endothelin (ET)-1 is a multifunctional peptide that exerts pleiotropic activities, including arterial and venous constriction, direct positive inotropic and chronotropic effects on isolated heart, and growth effects on vascular smooth muscle cells, fibroblasts, and isolated cardiomyocytes.1 Prepro–ET-1 (ppET-1) mRNA is expressed by both rat and human cardiac myocytes and interstitial cells that synthesize and secrete mature ET-1.2 3 4 The protease that catalyzes the conversion (ET-converting enzyme, ECE) from the 38-residue inactive intermediate big ET-1 to achieve ET-1 is expressed in the endocardium and myocardium.5 The differing biological activities of ET-1 appear to be mediated through 2 receptor subtypes (ETA and ETB),6 which are both present in the human myocardium and that of other species.7 Thus, a complete ET-1 system is represented in human myocardium.
Cardiac ppET-1 mRNA expression and ET-1 synthesis have been found to be increased in experimental hypertrophy by pressure overload8 9 10 and in experimental models of congestive heart failure (CHF),11 12 13 thus suggesting that the cardiac ET-1 system may be involved in cardiac diseases.
There have been very few investigations of the cardiac ET-1 system in human hypertrophy and heart failure. Expression of mRNA for ppET-1 and cardiac ET-1 formation have been found to be increased in hypertrophy with parietal wall stress <90 kilodyne/cm2 because of aortic valve stenosis.4 In situ hybridization has shown that ppET-1 mRNA is expressed in myocytes and to a lesser degree also in vascular and interstitial cells.4 Several studies have investigated cardiac ET-1 receptors. In endomyocardial bioptic specimens from patients with hypertrophic cardiomyopathy, mRNA expression for ETA receptors was not different from controls.14 ET-1 receptor subtypes have recently been investigated in myocardial homogenates of hearts from patients with end-stage idiopathic dilated cardiomyopathy (DCM)15 16 17 or ischemic cardiomyopathy (ICM),15 with conflicting results. Thus, despite the great potential pathophysiological and clinical implications of the cardiac ET-1 system,18 information about its functional activity in heart failure is lacking. Two factors might be critical in the study of the ET-1 system in this setting, as follows: first, a separate analysis of ET-1 receptors for myocytes and nonmyocyte myocardial cells, and second, investigation of the cardiac ET-1 system in relation to the etiology and severity of cardiac failure. The present study was therefore designed to investigate the functional activity of the cardiac ET-1 system in patients with DCM and ICM at different stages of heart failure severity. To this end, cardiac ET formation and receptor binding were evaluated and mRNA levels of ppET-1, ECE-1, ETA, and ETB receptor subtypes were quantified separately in isolated cardiomyocytes and in homogenated hearts.
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Materials and Methods |
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We investigated 42 patients with heart failure afflicted with DCM (n=22) or ICM (n=20) who were scheduled to undergo cardiac transplantation. Patients with arterial hypertension, a recent history (<6 months) of myocardial infarction, or echocardiographic evidence of valve or congenital heart disease were not considered for the study. The control group was made up of 20 normotensive patients with atypical chest pain in whom angiography and routine diagnostic procedures did not reveal any abnormalities. Diagnosis of DCM or ICM was based on clinical and echocardiographic examination, cardiac catheterization, and coronary angiography.
Myocardial ventricular tissue was collected from patients
with DCM and ICM during cardiac transplantation. Cardiac specimens were
also obtained from 7 donors with no histories or signs of heart
disease, whose hearts could not be transplanted because of surgical
reasons or blood group incompatibility (nonfailing [NF] hearts)
(Table 1
). The protocol of this study complies with the
principles of the Helsinki declaration. All patients gave their
informed, written consent to participate and to have their heart and
blood samples used for the study. Echocardiographic and
hemodynamic measurements were performed prospectively,
as previously described.4
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The estimation of cardiac ET-1 formation was performed by measuring the
aorta-coronary sinus gradient of ET-1 and big ET-1 corrected
for coronary flow and cardiac mass.4
Cardiomyocytes were isolated and membrane suspension was prepared from
a noninfarcted portion of left ventricle free wall.19
Binding studies were performed at equilibrium using selective
ETA (BMS-182874, a gift of
Bristol-Myers-Squibb) or ETB (BQ-788)
antagonists.19 mRNAs for ppET-1, ECE-1,
ETA, and ETB receptors,
extracted with phenol-chloroform from transmural myocardial specimens,
were quantified with Northern blots, using
-32P–labeled gel-purified specific cDNA
probes.
Levels of ppET-1, ECE-1, ETA, and ETB messengers were also quantified both in the myocardium and in isolated myocytes by reverse transcription–polymerase chain reaction (RT-PCR)4 using specific primers.17 The densitometric ratio was calculated using GAPDH as internal standard and expressed as the percentage of the values obtained in NF hearts.4 The in situ hybridization procedure was performed as previously described4 using specific cDNA photobiotin-labeled (Vector) probes. Myocardial cell types were identified by immunohistochemical methods using specific monoclonal antibodies. The average myocyte diameter was obtained by measuring the short-axis length of 200 myocytes using a computerized image-analysis system (Qwin, Leica).
Data are expressed as mean±SD. Comparisons between groups were performed using 1-way ANOVA. For multivariate re-evaluation of univariate correlations age, left ventricular end-diastolic diameter index, left ventricular mass index, left ventricular ejection fraction (LVEF), mean midwall velocity of circumferential fiber shortening (Vcf), mean pulmonary artery pressure, pulmonary capillary wedge pressure, average myocyte diameter, ET-1 and big ET-1 cardiac production, and concentration of ET-1 in venous blood were entered in a stepwise multiple regression analysis as independent variables considering ETA and ETB receptor densities on cardiomyocytes and membranes as dependent variables.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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Plasma Assays of Cardiac ET-1 and Big ET-1 Formation
The clinical characteristics of investigated subjects are reported in Table 1
. ET-1 and big ET-1 plasma concentrations in peripheral veins of ICM (3.1±1 and 15.2±3.3 pg/mL) and DCM patients (2.8±0.9 and 17.2±4.1 pg/mL) were higher than in controls (0.79±0.4 and 4.7±1.6 pg/mL, P<0.001 for both), with no significant differences between the 2 patient groups.
The mean aorta-coronary sinus concentration gradient of ET-1
was not significantly different among the 3 groups. Conversely, the
concentration gradient of big ET-1 was significantly higher in ICM
(1.7±1.1 pg/mL, P<0.001) than in DCM patients (-1.4±1.8
pg/mL, P<0.001) or controls (-0.04±0.23 pg/mL) (Figure 1A). The mean highest concentration
gradient of big ET-1 was found in ICM and the lowest in DCM patients,
as well as the amount of big ET-1 formed per minute per gram of tissue
(Figure 1B).
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) cardiac formation in
controls (C) and in patients with ICM and DCM. Statistical significance
in ET cardiac generation in comparison with controls is reported at top
of columns. *P<0.05 vs controls in multiple-comparison
test.
Radioligand Binding Studies
The density of ET-1 binding sites (Bmax) on
myocytes isolated from the left ventricle of NF hearts was 42±6
fmol/mg protein with 86% of ETA subtype (Table 2). Cardiac membranes from NF hearts had
an ET-1 binding site density (Bmax) of 195±25
fmol/mg with balanced proportions of ETA (63%)
and ETB (37%) (Table 2 and Figure 2A).
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), and
BQ-788 (
). Points are mean±SD of experiments performed in the 7 NF
hearts. B, ETA (•) and ETB (
The density of ET-1 binding sites on myocytes was significantly higher
in ICM than DCM or NF hearts (Table 2). Both
ETA and ETB subtypes were
increased in the same proportion (+45% and +50%, respectively)
(Figure 2B). The affinities of both subtypes were not
significantly different among the various groups (Table 2).
Membranes from ICM hearts showed significantly higher binding site
density than DCM (P<0.01) or NF (P<0.01) hearts
(Table 2) without any differences in the affinity with a
proportional increase of both ETA (+62%,
P<0.01) and ETB (+59%,
P<0.01) (Table 2). The individual data of the
receptor densities are shown in Figure 2B.
Multivariate stepwise analysis revealed that
ETA and ETB receptor
density on both myocytes and membranes from ICM hearts was positively
correlated with LVEF, whereas in DCM hearts only
ETB receptors demonstrated this positive
correlation (Table 3 and Figure 2C). ETA receptor density was positively
correlated with myocyte diameter in both ICM (r=0.80,
P<0.01) and DCM (r=0.66, P<0.01)
hearts. No correlation was found among ETA and
ETB myocyte or membrane receptor density and
plasma concentration or cardiac production of ET-1 and big
ET-1.
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Quantification of ppET-1, ECE-1, ETA, and
ETB mRNA Levels in the Myocardium and in
Isolated Cardiomyocytes
RT-PCR revealed that ppET-1, ECE-1, ETA, and
ETB receptor genes were expressed on myocytes
isolated from all the ventricles. Levels of mRNA for ppET-1, ECE-1,
ETA, and ETB receptors were
significantly increased in myocytes from ICM hearts
(P<0.001 versus NF hearts for all) but were not in myocytes
from DCM hearts. No significant differences were found between DCM and
NF hearts (Figure 3A).
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RT-PCR performed on homogenated hearts showed a lower
ETA/ETB mRNA ratio than in
isolated myocytes, with an increased expression of both
ETA and ETB mRNAs in ICM
hearts (Figure 3A). mRNA for ppET-1 was also increased in ICM
hearts, whereas no differences were found for ECE-1 mRNA expression in
comparison with DCM and NF hearts (Figure 3A). Northern blots
performed in myocardial samples confirmed the increased expression of
mRNA for ppET-1, ETA, and
ETB in ICM as compared with DCM and NF hearts
(Figure 3B).
In Situ Hybridization Studies
The average myocyte diameter was larger in ICM (20.1±1.8
µm) than in DCM (17.2±0.9 µm, P<0.001) and NF
(15.2±1.4 µm, P<0.001) hearts. Negative and
positive controls for hybridization showed that the hybridization
signal was specific for mRNA, and mRNA in the biopsies was intact
(Figure 4A and 4B).
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In NF (Figure 4C and 4D) and DCM (Figure 4G and 4H)
hearts, ppET-1 and ECE-1 mRNAs were mainly expressed on the
interstitial and endothelial cells, whereas
in ICM specimens a positive signal was also present in myocytes
(Figures 4E and 4F). In NF hearts, ETA receptor
mRNA was expressed on both myocyte and nonmyocyte cells (Figure 5A), whereas ETB
receptors were almost exclusively localized on nonmyocyte cells
(Figure 5B). In ICM specimens, mRNA both for
ETA (Figure 5C) and
ETB (Figure 5D) subtypes had the same
localization as observed in DCM specimens (Figure 5E and 5F) and
NF hearts. The intensity of the signal was higher in ICM specimens than
in the other groups.
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Discussion |
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The present study establishes the following for the first time in humans: (1) the presence, distribution, and characterization of ET-1 receptor subtypes in ventricular myocytes from NF hearts; (2) the different pattern of ET-1 receptors on myocytes and ventricular membranes in ICM versus DCM; and (3) the selective activation of the cardiac ET-1 system in ICM and its changes in relation to the progressive worsening of heart failure.
Myocyte ET-1 Subtype Receptors
Binding studies and densitometric analysis for mRNA
indicated that both ETA and
ETB receptors are represented in
ventricular myocytes from NF hearts, with a marked
predominance of ETA (86% versus 14%). The
absolute density of ET-1 receptors was higher in membranes than in
myocytes, with a more balanced proportion between
ETA and ETB (63% versus
37%). The different ratio of ETA and
ETB receptors in membranes and isolated myocytes
may point to different functions of the 2 receptor subtypes. There is
evidence that ETA receptors mediate the positive
inotropic and growth-promoting effects of ET-1.16 20 21
The close relationship found in the present study between myocyte
ETA receptor density and myocyte diameter
corroborates this role of ETA.
The function of ETB receptors is not yet completely clear. Several studies have suggested that ETB receptors may act as clearance receptors for ET-1,22 and the observation that ET-1 binding to ETB receptors is less stable than its binding to ETA receptors19 supports the above hypothesis. Because the total density of ETB receptors is higher in ventricular membranes than in myocytes, it may be speculated that ETB receptors may contribute to preventing excessive ET-1 myocardial concentrations.
The modifications of ventricular ET-1 binding sites occurring in CHF, particularly in DCMs, have been studied on ventricular homogenates. The different densities of ET-1 binding sites and the different proportion between ETA and ETB receptors on myocytes versus ventricular membranes may be the cause of the discrepancies among the various studies.15 16 17 Indeed, the densities of ET-1 binding sites in membranes from ICM and DCM hearts have not been found to differ significantly from those in NF hearts.15 Other studies performed in DCM hearts have reported either increased ETA density and ETB downregulation without any significant changes in the total density,17 or enhanced total density due to ETA increase without any modifications of ETB receptors.16 The separate analyses for myocytes and membranes, as performed in the present study, demonstrate that ET-1 binding sites are increased only in ICM hearts, with a proportional increase in ETA and ETB receptors both on myocytes and membranes and with changes correlated to LVEF.
Upregulation of Cardiac ET-1 System and Its Functional
Meaning
The increased density of ETA and
ETB receptors on myocytes and
ventricular membranes and the overexpression of mRNA for
ppET-1 and ECE-1 on myocytes indicate an upregulation of the cardiac
ET-1 system in ICM patients, resulting in an accelerated cardiac
synthesis of ET-1, as shown also by the increased big ET-1
aorta-coronary sinus gradient. The absence of an accompanying
increase in the ET-1 aorta-coronary sinus gradient does not
contradict this statement, because it may be due to the increased ET-1
degradation, to the enhanced binding of ET-1 to its receptors, or to
both. Because ET-1 degradation was not investigated, this hypothesis
cannot be excluded. However, the increased density of
ETA and ETB receptors both
on myocytes and ventricular membranes suggests an enhanced
capture of ET-1 by binding sites rather than an increase in ET-1
degradation. This mechanism would be consistent with the
increased ET-1 concentration in cardiac tissue reported in failing
myocardium15 23 24 and with the finding that
DCM patients, who showed neither enhanced cardiac ET-1 formation by
myocytes nor increased receptor density, had instead a significantly
lower coronary sinus gradient for big ET-1 than controls. In
these patients, whose mRNA for ECE-1 was not significantly different
from NF hearts, the negative gradient for big ET-1 was associated with
an ET-1 gradient that did not differ from that of controls or ICM
patients, suggesting an increased conversion of plasma big ET-1 to ET-1
during the transcardiac passage. Upregulation of mRNA for
ppET-1, increased peptide ET-1 level, and enhanced ET-1 receptor
density were found in the myocardium from rats with the
coronary artery ligation model of CHF.25 26 27 28
Conversely, ventricular ET-1 receptor density and myocyte
ET-1 production in pigs with pacing-induced CHF were not
different from those in control pigs.12 The present
results are thus consistent with experimental observations and
emphasize the different pattern of the cardiac ET-1 system in ICM
versus DCM patients.
ET-1 binding sites on cultured myocytes are downregulated by pretreatment with ET-1,29 and the level of ETB receptor mRNA is downregulated by ET-1 through decreasing the intracellular stability of mRNA molecules.30 In ICM patients, ETA and ETB receptors on both myocytes and membranes were not downregulated, despite the elevated ET-1 plasma levels. Only in patients with very low ejection fraction was the receptor density in the range of that of NF hearts. The precise mechanism determining the lack of ET-1 receptor downregulation is not clear. Cardiac ET-1 formation may be induced by different stimuli, including mechanical forces, hypoxia, and angiotensin II,31 which may be operating in ICM patients and may also upregulate the ET-1 receptors. Thus, it may be speculated that when the cardiac ET-1 synthesis is activated by locally acting stimuli, the local mechanisms of regulation predominate over the downregulation induced by plasma ET-1 levels. However, specially designed studies are needed to investigate this issue.
The upregulation of the cardiac ET-1 system seems to be important in the maintenance of the cardiac function in ICM patients, as indicated by the positive correlation of ETA receptor density with LVEF and Vcf and, conversely, the negative correlation between ETA receptors and left ventricular end-diastolic diameter index. The functional importance of cardiac ET-1–system activation seems to be confined to the normally functioning myocytes or to providing short-term support to failing myocardium.13 32 The favorable activity of ET-1 on cardiac function does not rule out the possibility that in the long term it may have adverse effects, because it has been shown to depress myocardial contractility and relaxation in pacing-induced CHF regardless of its effect on arterial load.33 Experimental studies have shown that the elevation of plasma ET-1 concentration, obtained by infusion, dose-dependently decreases myocyte contractility in pigs with pacing-induced CHF,12 and the long-term administration of various selective ETA antagonists in experimental models of CHF in different animal species prevents the contractility depression on both isolated myocyte34 and left ventricle.34 35 36 37
Although the ET-1 cardiac system was not upregulated in DCM patients, both ET-1 and big ET-1 plasma concentrations were similarly increased in ICM and DCM patients. The similar increase in ET-1 plasma levels in ICM and DCM patients, reported also in previous studies,23 38 reflects the severity of heart failure,23 especially the increase in pulmonary arterial pressure,38 and the endothelial dysfunction,39 but not the type of cardiomyopathy.
Mechanisms of Cardiac ET-1 Activation
The present investigation extends current knowledge
regarding the role of ET-1 in the pathophysiology of severe heart
failure. The widely different pattern of the ET-1 system in ICM and DCM
patients is not attributable to apparent clinical,
echocardiographic, and hemodynamic
differences, because the 2 groups of patients did not differ either for
these parameters or for the drugs administered. Thus, it is
reasonable to conclude that heart failure is not in itself responsible
for cardiac ET-1 system activation, which is probably instead due to
the primary disease underlying the heart failure. There is evidence
that mechanical forces selectively induce cardiac growth factor
synthesis in relation to pressure or volume
overload.4 40 41 Although ICM consists of a complex
mixture of ischemia, stress due to myocardial scar, and often a
component of volume overload,42 myocytes are substantially
subjected to stretch because of pressure overload, given that the
residual healthy myocytes are forced to face a greater workload to
compensate for the loss of neighboring contractile elements resulting
from myocardial infarction and chronic myocardial ischemia.
Experimental and human pressure-overload hypertrophy is
associated with an increased ET-1 formation.4 8 9 In
addition, in experimental severe heart failure induced by
coronary artery ligation, an increased expression of ppET-1
mRNA was reported in nonischemic myocardial
areas.25 28 Hypoxia and acute experimental
ischemia have each been reported to induce ET-1 formation in
isolated myocytes43 or ventricular
myocardium.44 However, ischemia does
not seem to be a major mechanism in the increased ET-1 formation in ICM
patients, because an ischemic component is present in the
heart of DCM patients45 46 and myocardial perfusion is
impaired both at rest and in response to vasodilating stimuli in DCM
patients.47 Therefore, pressure overload seems to be a
major mechanism of cardiac ET-1 system activation in ICM.
The inciting factor of DCM is unknown, but this condition is characterized by ventricular remodeling producing chamber dilation with normal or decreased wall thickness. The resulting eccentric hypertrophy45 48 suggests volume overload as a prevalent hemodynamic mechanism. Patients with predominant volume-overload hypertrophy, like those with aortic regurgitation, show no evidence of increased myocyte ET-1 formation.4
Hence, although we cannot exclude other mechanisms, including the incapacity of myocytes from DCM patients to produce ET-1 in response to mechanical forces or cardiac and humoral factors, the different type of hemodynamic overload would seem to be the major mechanism responsible for the different patterns of the cardiac ET-1 system in cardiomyopathies.
In conclusion, the cardiac ET-1 system is selectively upregulated in ICM patients, whereas it is not in DCM patients, and it appears to be functionally important for the maintenance of cardiac function in the former.
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Acknowledgments |
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The financial support of Telethon—Italy (grant 864) and of the Ministero dell’Università e della Ricerca Scientifica (project 9806103104) is gratefully acknowledged. X.J. was the recipient of a research fellowship from the Ministero degli Affari Esteri of Italy (grant 22478bis).
Received September 16, 1999; accepted December 8, 1999.
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