(Circulation. 1995;92:175-182.)
© 1995 American Heart Association, Inc.
Articles |
Prerequisite for Cardiac Aldosterone Action
Mineralocorticoid Receptor and 11ß-Hydroxysteroid Dehydrogenase in the Human Heart
From INSERM U246, Institut Fédératif de Recherche "Cellules épithéliales," Faculté de Médecine X. Bichat, Paris, France.
Correspondence to Marc Lombès, INSERM U246, Faculté de Médecine X. Bichat, 16, rue H. Huchard, BP 416, 75870 Paris, CEDEX 18, France.
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Abstract |
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Background It has been proposed that aldosterone exerts direct effects on heart function, most notably on the development of myocardial fibrosis during ventricular hypertrophy in rat. Initial events in aldosterone action entail its binding to mineralocorticoid receptor (MR). Because MR displays similar affinities for aldosterone and glucocorticoids, the in vivo aldosterone selectivity of MR requires the presence of an enzyme, 11ß-hydroxysteroid dehydrogenase (11-HSD), which metabolizes glucocorticoids into inactive derivatives. Although evidence exists for the presence of MR in rodent heart, no data are available for humans; moreover, the existence of cardiac 11-HSD is controversial.
Methods and Results The heart samples used originated from tissue removed during cardiac surgery in nontransplant patients or from endocavitary biopsies done for the follow-up of heart transplantation. The expression of MR was examined at the mRNA and protein level by in situ hybridization with cRNA probes specific for human MR mRNA and by immunodetection with two specific anti-MR antibodies. 11-HSD catalytic activity was determined by measurement of the metabolic rate of tritiated corticosteroids by cardiac samples. In nontransplanted hearts, an in situ hybridization signal equivalent to that found in the whole kidney was present on cardiomyocytes. Specific immunolabeling of cardiomyocytes with anti-MR antibodies demonstrated the presence of the MR protein. Cardiac 11-HSD activity was detected (243±26 fmol · 30 min-1 · mg protein-1) and was dependent on the cofactor NAD, not NADP, suggesting that it corresponds to the form of the enzyme specifically responsible for MR protection. In transplanted hearts that presented severe alterations, MR immunodetection was weaker and irregular, with no specific hybridization signal.
Conclusions Our results demonstrate that MR is coexpressed with 11-HSD in human heart, which thus possesses the cellular machinery required for direct aldosterone action.
Key Words: adrenal cortex hormones • glucocorticoids • transplantation • antibodies • enzymes
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The mineralocorticoid hormone aldosterone exerts its known effects in epithelial cells via an intracellular receptor, the mineralocorticoid receptor (MR). The main effect of the hormone is to promote renal sodium reabsorption in exchange for potassium.1 In addition to its classic effects on epithelial cells, such as those of the kidney and the colon, it has been shown more recently that aldosterone binds to specific receptors in nonepithelial tissues, such as the heart2 3 4 5 or the hippocampus of the brain.6 It has been established that elevated plasma aldosterone is associated with the pathogenesis and progression of human heart failure.7 In addition to the indirect effects of aldosterone on cardiac function during heart failure resulting from sodium retention, expansion of extravascular space, and hypervolemia, some experimental evidence suggests that this hormone may exert direct effects on the heart. Some reports8 9 10 favor a role of aldosterone on rat muscle contractility and membrane potential, although its steroid specificity is unclear. In cultured rat cardiomyocytes, aldosterone stimulates the biosynthesis of the Na+,K+-ATPase
1 subunit.11 Recently, Brilla et
al12 13 14 demonstrated that in rats with
experimentally
induced left ventricular hypertrophy, elevated levels of plasma
aldosterone (and/or renin-angiotensin) led to the development of
cardiac fibrosis. It was proposed that this effect represents a
direct mineralocorticoid action on the heart, since administration of
the aldosterone antagonist spironolactone suppressed it at doses that
did not reduce arterial hypertension.14 The
mineralocorticoid specificity of this effect was confirmed in another
recent study.15 The mechanism involved could be an
aldosterone-induced stimulation of collagen synthesis, possibly by the
cardiofibroblasts.12 15 16 The direct
demonstration of an
increase in rat cardiac types I and III collagen mRNAs in
aldosterone-salt hypertension17 supports this
hypothesis. Direct effects of aldosterone on heart indeed require the presence in cardiac cells of its specific receptor, the MR. Several experimental studies show that this is the case. Specific binding of aldosterone to MR (or high-affinity type I sites) has been reported in rat2 3 4 and rabbit5 heart. Autoradiographic localization of aldosterone binding sites has been shown in the rat heart.18 Immunodetection of MR was evidenced in the four cavities of rabbit heart by use of H10E, a specific anti-idiotypic antibody against MR.5 In addition, the presence of MR mRNA has been established by Northern blot analysis in the rat heart.19 20
An increasing body of evidence indicates that the specific expression of aldosterone effects in target tissues depends on the enzyme 11ß-hydroxysteroid dehydrogenase (11-HSD). Indeed, natural glucocorticoid hormones (corticosterone, cortisol) display an affinity for the MR similar to that of aldosterone itself,21 and their circulating levels are much higher than that of aldosterone. By locally metabolizing glucocorticoids into derivatives (cortisone, 11-dehydrocorticosterone) with low affinity for MR, 11-HSD allows MR to remain free for aldosterone binding and specific action.21 22 The demonstration of coexpression of MR and 11-HSD in the typical aldosterone target cells of the distal nephron of the kidney23 24 argues in favor of the MR-protecting role of this enzyme. The presence of 11-HSD activity in the rat heart is controversial, since some authors did not detect it21 22 and others did.25 26 27 28 In addition, it has recently been demonstrated that at least two forms of the enzyme exist, with different enzymatic properties, especially concerning their dependence on either the cofactor nicotinamide-adenine dinucleotide (NAD) or nicotinamide-adenine dinucleotide phosphate (NADP).29 30 31
In contrast to animal studies that report on MR expression in the heart likely to mediate direct action of aldosterone on this organ, such information is not yet available for humans.
The aims of the present study were (1) to determine whether MR is expressed in human heart at the mRNA and protein levels and (2) to examine whether 11-HSD activity could be detected and to determine its cofactor dependence. Our results demonstrate that both MR and an NAD-dependent 11-HSD activity are present in cardiomyocytes of human heart.
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Methods |
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Myocardial biopsies have been obtained during cardiac surgery or from endocavitary catheterization. In an initial series of investigations, it was possible to obtain fragments of left ventricular biopsies performed in patients with heart transplants for the systematic follow-up of transplant tolerance. Biopsies were fixed in Zamboni fixative (as previously described in Reference 5) and processed either for in situ hybridization or for immunodetection of MR, in addition to the microscopic examination of the biopsy. In some cases, small fragments of these biopsies were obtained for direct assessment of the catalytic activity of the enzyme 11-HSD. Because MR expression was variable in these conditions, another series of investigations was conducted on heart tissue from nontransplanted patients undergoing cardiac surgery for valve repair (essentially mitral valve surgery). Small pieces of atrium or left ventricle were processed as described above either for MR detection or for measurements of 11-HSD activity.
In Situ Hybridization
Heart sections (5 to 7 µm) were cut
and mounted on subbed
slides and processed for in situ hybridization as previously
described.32 Briefly, after removal of paraffin with
xylene, sections were rehydrated in graded alcohols followed by PBS.
Sections were postfixed again in 4% paraformaldehyde for 20 minutes
and rinsed in PBS. Next, treatment with proteinase K (20 µg/mL) was
followed by an acetylation step (0.1 mol/L triethanolamine, pH 8,
0.025% acetic anhydride). After they were rinsed in PBS and 0.9%
NaCl, sections were dehydrated and dried. Hybridization mix was then
spread over the sections, and the slides were covered with paraffin
film. Sections were hybridized for 16 to 18 hours at 50°C.
Posthybridization treatment consisted of an initial wash in 5x saline
sodium citrate (SSC; 150 mmol/L NaCl, 15 mmol/L sodium citrate), 10
mmol/L dithiothreitol (DTT) at 50°C, a high-stringency wash in 50%
formamide, 2x SSC, 0.1 mol/L DTT at 65°C for 20 minutes, and two
10-minute washes in NaCl-Tris-EDTA (0.5 mol/L NaCl, 10 mmol/L Tris-HCl,
5 mmol/L EDTA) at 37°C. Ribonuclease A treatment (20 µg/mL) was
then performed at 37°C for 10 minutes. After being rinsed with 0.1x
SSC for 15 minutes, sections were dehydrated in graded alcohols
(containing ammonium acetate 0.3 mol/L) and dried. Kodak NTB2 film
(melted at 42°C) was applied to the slides, dried, and exposed at
-20°C for 3 to 6 weeks. The film was developed (Kodak D19) and fixed
(Kodak Unifix). At the end of the autoradiographic process, the
sections were stained with toluidine blue.
Human MR (hMR) cDNA, kindly provided by Dr R. Evans (Salk Institute, Howard Hughes Medical Center, La Jolla, Calif), was cut by Sca I, and the fragment (nt398-1205) was subcloned into PGEM (Promega) to synthesize antisense (complementary to the tissue hMR mRNA) or sense (similar to the hMR mRNA) cRNA probes. This region of the cDNA, corresponding to the N-terminal region of the receptor, is not homologous to the glucocorticoid cDNA sequence (46.7% identity at the nucleotide level). After linearization, 35S-labeled RNA probes were synthesized by use of SP6 or T7 polymerase. 35S-labeled UTP 5'-triphosphate (>37 TBq/mmol) was from Amersham, and the other reagents (ATP, GTP, CTP, ribonucleasin, DTT, and RNA polymerases) were from Promega. The hybridization mix was 50% formamide (Fluka), 1 mmol/L DTT (Boehringer), 2x SSC, 10% dextran sulfate (Pharmacia), 1 mg/mL salmon sperm DNA (Sigma), and the 35S-labeled cRNA. Immediately before hybridization, this mix was denatured at 80°C for 5 minutes. Approximately 1x106 to 2x106 cpm was applied to each slide.
Quantification of the hybridization signal was performed by image analysis (Optilab, Graftek). Results are given as arbitrary units per surface area. Background was measured on the slide on a zone without tissue and deducted from tissue labeling. Similar analysis was done in sections from the same tissue hybridized with antisense and with sense probe. Specific signal is the difference between these two conditions.
In addition to heart biopsies, human kidney tissue obtained from the nontumoral portion of a surgically removed kidney was hybridized on the same slides in parallel with heart sections.
Immunodetection of MR
Five- or 7-µm sections were cut,
mounted on slides, and
processed for immunohistochemistry. A routine procedure of indirect
immunostaining was applied essentially as
described.2 33 34 Briefly, incubation
with the primary
antibodies was followed by a horse-biotinylated anti-mouse or
anti-rabbit antibody human adsorbed (Vector Laboratories Inc), and an
avidin-biotin-peroxidase complex (ABC-Elite from Vector Laboratories)
was used as a detection system.
The following antibodies were used: H10E, a monoclonal anti-idiotypic antibody of the IgG1 class that interacts with the steroid binding domain of the MR,35 and A4, a rabbit polyclonal antibody directed against a peptide corresponding to the hMR412-422,36 ie, in the N-terminal region of the receptor molecule. The control of the specificity of the immunolabeling was performed by presaturating the anti-peptide antibodies A4 with the free peptide at a concentration of 100 µg/mL. Because H10E is an internal image of aldosterone,35 in situ competition studies could be performed to assess the specificity of immunolabeling. This was achieved by preincubating the slides with 1 to 5 µmol/L aldosterone in PBS for 30 minutes before incubation with H10E.
Determination of 11-HSD Catalytic Activity
Enzyme activity
was measured by determining the rate of
transformation of tritiated corticosterone into
11-dehydrocorticosterone as described
previously.23 37
Small pieces of heart (<3 mg each) were incubated in 100 µL of
solution (in mmol/L: NaCl 137, KCl 5, MgSO4 0.8,
Na2HPO4 0.33, KH2PO4
0.44, MgCl2 1, CaCl2 1, D-glucose
5, and Tris-HCl 10; pH 7.4) with 10 nmol/L
3H-corticosterone (1,2,6,7-3H-corticosterone,
2.22 TBq/mmol, Amersham) at 37°C. Samples of supernatant (5 µL)
were carefully removed at various time intervals and transferred into
95 µL methanol, to which 10-4 mol/L unlabeled
corticosterone and 11-dehydrocorticosterone were added to serve as
internal standards for high-performance liquid chromatographic
analysis (Beckman Gold HPLC system). Samples (100 µL) were
injected onto a reverse-phase column (Novapak C18, Waters Associates)
with a precolumn (C18, 5 µm; Waters) and eluted isocratically with
methanol-H2O (1:1) at 1 mL/min. UV absorbance was recorded
at 240 nm to monitor the elution time of internal standards for each
sample. Eluate from the column was collected at 30-second intervals,
and radioactivity was counted (LKB Rackbeta) after the addition of 3 mL
Optiphase (LKB). The eventual spontaneous metabolism in the incubation
medium was evaluated by its incubation with steroids in the absence of
tissue (blanks) and appeared to be very low (generally <0.5%). In
some cases, an inhibitor of 11-HSD (carbenoxolone, 10-4
mol/L, Sigma) was added to the incubation medium. To test the cofactor
specificity of the heart 11-HSD, the enzyme was measured after
permeabilization of the tissue (three consecutive freezing-thawing
procedures) in the absence and in the presence of 1 mmol/L NAD or
NADP.
Results are expressed as femtomoles of 11-dehydrometabolites produced per milligram wet weight or per milligram protein. The protein content of each sample was measured by the method of Bradford38 at the end of the incubation and after solubilization in NaOH.
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Results |
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In Situ Hybridization
Figs 1
and
2 illustrate the results
obtained after hybridization of heart from nontransplant patients and
kidney sections with antisense and sense hMR specific probes. A clear
labeling by the antisense probe is present over atrial and left
ventricular myocytes (Fig 1), contrasting with a very low
signal over
intramyocardial vascular structures. The control or sense probe clearly
gave a lower signal. For purposes of comparison, the labeling obtained
in the kidney with these same two probes is shown in Fig 2. The
antisense probe strongly labeled the typically
mineralocorticoid-sensitive cortical collecting duct and distal
tubules,1 33 with low nonspecific labeling of
proximal
tubules and glomeruli, thus establishing its adequacy to detect hMR
mRNA. The sense probe gave a low and homogeneous signal all over the
sections. As for human heart, a positive signal associated with the
antisense hMR probe was found in all heart biopsies originating from
seven patients undergoing mitral valve replacement.
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Quantification of
in situ hybridization experiments is shown in Fig 3. The
antisense signal was clearly much higher than the
sense labeling in each biopsy, although absolute levels vary among
patients. The Table gives the mean values of specific
hMR mRNA signals (antisense minus sense labeling) in heart and kidney.
With respect to the whole organ, hMR mRNA levels are roughly equivalent
in heart and kidney cortex. In contrast to the heart, however, the
signal is quite heterogeneous within the kidney, since only a small
proportion of the tubular cells express hMR mRNA. As shown in Fig
2
,
the messenger is indeed restricted to the distal tubule and cortical
collecting duct, which represent a small percentage (<10%) of
the total mass of the kidney cortex. In these particular
aldosterone-sensitive cells, the labeling per unit surface area was 4
to 5 times higher than over myocytes.
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The same hybridization protocol was performed on sections of ventricular biopsies from nine different heart transplant patients undergoing polytherapy, including corticosteroids. In each case, the hybridization signals were similar with the antisense and the sense probe. Thus, no reproducible specific signal could be detected in this group of patients.
Immunolocalization of MR
Fig 4 shows the
immunolabeling obtained with
the antipeptide antibody A4 and the monoclonal anti-idiotypic anti-MR
antibody H10E on sections of cardiac tissue from nontransplant
patients. A clear immunostaining was observed with both antibodies on
myocytes, whereas small intraventricular vessels lack specific
labeling. The extinction of labeling achieved by preincubation with the
peptide (for A4) or aldosterone (for H10E) results in a background
signal similar to that obtained with unrelated primary antibodies, thus
attesting to the specificity of MR detection. Similar results were
obtained in samples from eight nontransplant patients.
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Experiments performed on fragments of biopsies from transplanted heart did not yield clear-cut and reproducible results. Profound disturbance of heart tissue was often observed in these biopsies, with edema and presence of fibrosis and inflammatory cells. Whereas a specific signal could be observed with H10E for some samples, immunolabeling was widely variable from one zone to another within one single biopsy and from one patient to another (data not shown).
11-HSD Catalytic Activity
11-HSD catalytic activity was
assayed on heart tissue from
nontransplant patients. Fig 5 shows the time dependence
of 11-HSD activity in permeabilized tissue incubated in the presence of
the cofactor NAD or NADP. Enzyme activity increased with incubation
time. Values were clearly higher in the presence of NAD than NADP. The
enzyme inhibitor carbenoxolone strongly reduced the NAD-dependent
enzyme activity. This cofactor dependence was further assessed in three
different patients tested, as illustrated in Fig 6.
Values in the presence of NAD (243±26 fmol · 30
min-1 · mg protein-1,
mean±SEM,
n=3) were twice as high as those observed in permeabilized tissue in
the presence and in the absence of NADP (99±13, n=3), as well as
in
intact tissue. Thus, it appears clear that the human heart 11-HSD is
NAD- and not NADP-dependent.
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In addition, it was possible to confirm the presence of 11-HSD on small fragments of left ventricle biopsies from some transplant patients. These experiments demonstrate a time-dependent, carbenoxolone-inhibitable 11-HSD activity in these transplanted heart samples (data not shown). The enzyme activity of intact tissue from five different patients reached a mean value (±SEM) of 13.8±3.6 fmol · mg wet wt-1 · 120 min-1 incubation with 3H-corticosterone, which was reduced to 1.2±0.8 in the presence of carbenoxolone.
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Discussion |
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The present study shows that the MR is expressed in human heart at both the mRNA and protein levels. When a specific cRNA probe encoding for the N-terminal portion of hMR was used, a clear-cut signal was observed on cardiomyocytes. This finding is coherent with a previous demonstration of MR mRNA by Northern blot in rat heart.19 20 The adequacy of the probe used was established by the specific labeling observed in the human distal nephron. Although the overall abundance of hMR mRNA was of comparable magnitude in heart and whole kidney cortex, the intensity of the hybridization signal was fivefold lower in cardiomyocytes than in the specific aldosterone target cells of the renal distal tubule.33 The MR was also found on cardiomyocytes at the protein level by immunohistochemistry using two different antibodies: H10E, which is specific to the steroid-binding domain of the receptor, and A4, which recognizes an N-terminal portion of hMR. No apparent variation in hMR mRNA or protein levels was found among tissue samples originating from the left ventricle, the papillary muscle of the mitral apparatus, or the right auricle. Neither mRNA nor immunoreactive hMR was detected over small intramyocardial blood vessels. This is in agreement with previous observations made on the rabbit heart.5 Whereas hMR was constantly and reproducibly found by both approaches in heart samples from nontransplant patients, this was not the case in transplanted hearts. Although positive immunostaining could be observed in some biopsies, wide variations in intensity and heterogeneous staining were observed from one fragment to another. Messenger RNA detection was weak and inconsistent. The reason for the variability of results in transplanted hearts is unclear. One might invoke the tissue alterations (edema, fibrosis), which affected, to a variable extent, the heart sections examined. In addition, the patients had received various polytherapies, including immunosuppressive agents as well as glucocorticoids, that might have modified MR expression.
Results of immunolabeling and in situ hybridization clearly indicate that MR is expressed in the whole population of cardiomyocytes. This is in accordance with previous data obtained with the anti-MR antibody H10E in rabbit heart.5 This previous report indicated that, in addition to cardiomyocytes, endothelial cells and other cell types (possibly cardiofibroblasts) also expressed MR. The present study neither confirms nor contradicts this observation. Moreover, no conclusions concerning endothelial cells could be reached because of the limited size of the samples. In addition, the available material did not permit us to examine precisely the possibility of a specific labeling on cell types other than cardiomyocytes, except for the negative results on intramyocardial small vessels. The MR localization in cardiomyocytes deserves discussion with regard to the reported aldosterone-induced cardiac fibrosis.12 13 Indeed, an enhanced rate of intracardiac collagen gene expression has been demonstrated in hypertrophied hearts of aldosterone-treated rats.17 On the other hand, aldosterone has been shown to increase collagen synthesis in rat cardiac cultured fibroblasts.16 The aldosterone-induced stimulation of collagen synthesis could depend on a direct effect of the hormone on cardiofibroblasts. Alternatively, aldosterone could modulate the functions of cardiomyocytes, leading to changes in the cell environment. In this case, the cardiac fibrosis should be considered a paracrinelike effect of this hormone.
In addition to the MR expression, the present study establishes the presence of 11-HSD dehydrogenase activity in the human heart. The existence of such an activity in the rat heart has been previously reported by several25 26 27 28 29 but not all21 22 authors. The question arises of evaluating the level of 11-HSD activity in heart compared with other tissues, particularly the classically aldosterone-sensitive tissues. However, such a comparison is difficult to make because of the large variations in experimental conditions from one study to another. Indeed, experiments are performed in a variety of preparations (microsomes, homogenates, intact or permeabilized cells), and results are given either as percent conversion of the glucocorticoid substrate (corticosterone or cortisol) or as the absolute value of the metabolite produced (dehydrocorticosterone or cortisone). Incubation times vary from a few minutes to several hours. This renders quantitative comparisons difficult, since substrate depletion could reduce enzyme activity after long incubation time. Finally, the glucocorticoid substrate concentration varies from the nanomolar range to above the micromolar range, a concentration generally considered as exceeding the Km.24 29 However, authors generally agree that in rat, dehydrogenase activity is much lower in the heart than in the kidney. Comparison of the present results with previous data from our laboratory37 obtained under similar experimental conditions in human tissue and recalculated in the same units is in accordance with this notion: 11-HSD dehydrogenase activity is about 100-fold lower in heart than in the typically aldosterone-sensitive renal collecting duct. Such a difference raises the question of the actual physiological role played by 11-HSD. This question cannot be resolved with certainty, since the answer depends on several parameters, some of which are still difficult to assess, such as the relative expression and regulation of 11-HSD and MR in a given cell type or the subcellular relative spatial distribution of the receptor and the enzyme. A growing body of evidence indicates that the MR-protecting role of 11-HSD, implied in mineralocorticoid selectivity, depends on the isoform of the enzyme.29 30 31 39 The prevailing notion is that at least two different isoforms of 11-HSD exist, with different enzymatic properties and different tissue and/or cell distribution. One of them exhibits low affinity for glucocorticoids, is relatively ubiquitous, but is particularly prevalent in the liver. According to the cell context, it can function as a dehydrogenase or reductase. It is thought to play little or no role in MR protection and might be involved in regulatory processes of glucocorticoid functions.39 Another form displays a high affinity for the glucocorticoid substrate. It has been found in placenta40 and in the aldosterone-sensitive renal cells29 30 31 and is considered to be the MR-protecting enzyme. Importantly, these two isoforms differ by their dependence on cofactors. The first one is NADP-dependent, whereas the latter, ensuring MR protection, is NAD-dependent. The present results clearly show that the form expressed in human heart is NAD- and not NADP-dependent and may therefore correspond to the MR-protecting form of the enzyme. This could explain why the natural glucocorticoid corticosterone, which displays the same affinity for the MR as aldosterone, does not induce cardiac fibrosis,15 while also supporting the claim for the mineralocorticoid specificity of the aldosterone-induced fibrosis.
In conclusion, the present study demonstrates the coexpression of MR and the MR-protecting NAD-dependent 11-HSD in the human heart. This coexpression does permit direct specific effects of aldosterone in the heart in physiological as well as pathological conditions, such as the aldosterone-induced development of fibrosis in hypertrophied left ventricle. These findings may open new therapeutic perspectives on the use of antimineralocorticoids in the prevention of cardiac fibrosis and heart failure.
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Acknowledgments |
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This work was supported by INSERM funds and by a grant from the Searle "Fondation pour l'hypertension artérielle." We wish to thank Dr A. Nitenberg for providing us with the human tissue samples. We are indebted to V. Lévêque for expert secretarial assistance, to F. Delahaye for her help in performing immunolocalization of mineralocorticoid receptor, and to T. Carlson for editing the manuscript.
Received October 18, 1994; revision received December 27, 1994; accepted January 10, 1995.
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