Published online before print September 13, 2004, doi: 10.1161/01.CIR.0000142858.44680.27
(Circulation. 2004;110:1819-1825.)
© 2004 American Heart Association, Inc.
Molecular Cardiology |
Cardiac Specific Increase in Aldosterone Production Induces Coronary Dysfunction in Aldosterone Synthase–Transgenic Mice
From INSERM U572, Université Paris 7 (A.G., J.K.B., J.N., M.-L.A., P.D., C.H., C.D.), INSERM U36, Collège de France (S.F.), INSERM U426, CEFI IFR02, Assistance Publique–Hôpitaux de Paris, Faculté de Médecine Bichat (B.E.), and Laboratoire d’hormonologie, Hopital St Louis (G.M.), Paris, France; INSERM U446, Faculté de Pharmacie, Châtenay-Malabry, France (F.R., J.H., R.F.); Instituto Mario Negri, Milano, Italy (N.D.A.); and INSERM U508, Institut Pasteur, Lille, France (F.P.).
Correspondence to Dr Claude Delcayre, INSERM U572, Hôpital Lariboisière, 41 Boulevard de la Chapelle, 75475 Paris cedex 10, France. E-mail claude.delcayre{at}larib.inserm.fr
Received April 7, 2004; revision received July 23, 2004; accepted July 28, 2004.
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Abstract |
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Background— Elevated circulating aldosterone level is associated with impaired cardiovascular function. Although the mechanisms are not fully understood, aldosterone antagonists decrease total and cardiovascular mortality in heart failure and myocardial infarction. Aldosterone induces cardiac fibrosis in experimental models, and it is synthesized locally in rat heart. These observations suggest pathological effects of aldosterone in heart that remain unclear.
Methods and Results— Transgenic mice (TG) that overexpress the terminal enzyme of aldosterone biosynthesis, aldosterone synthase (AS), in heart have been raised by gene targeting with the 
-myosin heavy chain promoter. AS mRNA increased 100-fold and aldosterone concentration 1.7-fold in hearts of male TG mice relative to wild-type. No structural or myocardial alterations were evidenced, because ventricle/body weight, AT1 and AT2 receptor binding, and collagen content were unchanged in TG. No alteration in cardiac function was evidenced by echocardiography, isolated perfused heart, or whole-cell patch clamp experiments. In contrast, coronary function was impaired, because basal coronary flow was decreased in isolated perfused heart (–55% of baseline values), and vasodilatation to acetylcholine, bradykinin, and sodium nitroprusside was decreased by 75%, 60%, and 75%, respectively, in TG mice compared with wild-type, showing that the defect was not related to NO production.
Conclusions— Increased cardiac aldosterone production in male mice induces a major coronary endothelium-independent dysfunction with no detectable alterations in cardiac structure and function. However, coronary dysfunction may be harmful for coronary adaptation to increased flow demand.
Key Words: aldosterone • hormones • genes • heart diseases
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Introduction |
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The Randomized ALdactone (spironolactone) Evaluation Study for congestive heart failure (RALES) study has shown that the mineralocorticoid-receptor (MR) antagonist spironolactone decreases mortality in patients with heart failure (HF).1 Decreased mortality was also observed in patients with left ventricular (LV) dysfunction after myocardial infarction (MI) treated with the mineralocorticoid receptor–specific antagonist eplerenone.2 In both studies, beneficial effects were obtained using doses of aldosterone antagonists that had no effect on blood pressure.
See p 1714
Aldosterone has deleterious effects on heart structure and function (reviewed by Delcayre and Swynghedauw).3 The mineralocorticoid receptor is present in heart, supporting the possibility that aldosterone may have actions on this organ independently of its renal and blood pressure effects. Experimentally, cardiac fibrosis is induced in aldosterone-salt–treated rats,4,5 but the mechanisms remain partly unclear.3 A pericoronary inflammatory phenotype is an early step of cardiac damage in aldosterone-salt–treated animals,6–8 suggesting that coronary arteries may be a target for aldosterone in heart.
Aldosterone is produced at low levels in rat heart,9 its production increasing after myocardial infarction, in which it participates in myocardial infarction–associated fibrosis.10,11 In humans, several steroidogenic genes are detected in the failing heart,12 and aldosterone synthase (AS) mRNA is upregulated in ventricles of patients with HF13 or with hypertrophic cardiomyopathy.14 Another study has linked the increase in cardiac aldosterone production to LV dysfunction.15 These observations strengthen the possibility that cardiac aldosterone may have harmful effects in the myocardium.
Until now, the effects of aldosterone on cardiac structure and function have been observed in experimental models based on increased plasma aldosterone plus salt. To better define the specific cardiac effects of aldosterone, we created a mouse model in which aldosterone was specifically increased in the heart without changes in its plasma level. Phenotypic analysis of these mice showed that AS overexpression induced a major coronary dysfunction without changes in cardiac structure and function in transgenic male mice.
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Methods |
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Detailed methods are included in the online-only Data Supplement to this article, which is available at http://www.circulationaha.org.
Transgenic Mice
Expression of the transgene containing the 1500-bp coding sequence of AS (Figure 1A) was driven by the mouse -MHC gene promoter.16 Two independent founder lines (8282 M and 8283 M) were established in FVB mice. The numbers of mice used in this study were 54 wild-type (WT) and 62 transgenic (TG). Separate groups of mice were used for phenotype studies and for cardiac perfusion and coronary studies.
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Collagen and Angiotensin II Receptor Assay
Quantification of collagen was determined as described previously.10 Binding analysis of angiotensin II (Ang II) receptors was performed as described previously.17 AT-receptor subtypes were identified by incubation with losartan or PD 123319.
RNA Analysis
Extraction of heart total RNA and reverse transcription-polymerase chain reaction of AS and 11-ß-hydroxylase were performed as described previously.10 Total RNA yields were not different in WT and TG mice.
Western Blot
Mitochondrial proteins were isolated from ventricles.18 Blots were incubated with an antibody against the rat AS that detected the mouse AS (kind gift of Dr Gomez-Sanchez, University of Mississippi Medical Center, Jackson). AS protein was detected with an ECL+ kit (Amersham).
Hormones
Aldosterone in cardiac homogenates was assayed by radioimmunoassay using a Immunotech kit (Beckman) and corticosterone with an in-house radioimmunoassay.
Echocardiography
Echocardiography was performed as published previously.19
Isolated Heart Perfusion
Contractile properties of hearts perfused in nonrecirculating Langendorff mode at constant pressure (80 mm Hg) were recorded as published previously.20
Coronary Function
Coronary vascular responsiveness to vasoactive agents was measured in nonrecirculating Langendorff mode at constant flow as published previously.21 Vasoactive drugs were administered by bolus injections just above the aortic cannula.
Electrophysiological Analysis of Calcium and Potassium Currents
Whole-cell patch-clamp of ventricular myocytes was used to record the L-type Ca2+ current (ICa,L) as published previously,20 and the time-dependent and time-independent components of the potassium transient outward currents, Ito1 and Isus, respectively, as published previously.22
Statistical Analysis
Results were expressed as mean±SEM. Data were analyzed by use of the Mann-Whitney rank-sum test, followed by a Student’s t test when appropriate. A value of P<0.05 was considered statistically significant, without any adjustment for multiple testing.
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Results |
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AS Overexpression
Two independent mouse TG founder lines (8282 M and 8283 M) were established. Postnatal development and basic phenotype parameters were similar in both TG lines. Results presented here were obtained in male mice of line 8282 M.
Figure 1B shows an increase of 
100-fold of the AS mRNA in ventricles of TG mice compared with age-matched WT. In WT samples, the 633-bp band contained 2 products: AS and 11-ß-hydroxylase. Their quantification, using AvaI, which cuts AS, and NheI, which cuts 11-ß-hydroxylase (not shown), gave an AS/11-ß-hydroxylase ratio of 1/7. Figure 1B shows that the 633-bp band in TG samples was much more intense than in WTs because of the presence of transgenic rat AS. AS mRNA was also induced in lung, but to a lower level than in heart, in agreement with the known -MHC expression in this organ,16 and was not detected in adrenal gland, kidney, skeletal muscle, and brain (not shown). AS was detected by Western blot only in TG mouse ventricles (Figure 1C). Aldosterone concentration in ventricles was increased by 1.7-fold in TG mice (Table 1). Aldosterone levels were increased identically in either left or right ventricles and left or right atria (not shown). Interestingly, there was neither a change in aldosterone concentration in adrenal glands or plasma nor a change in corticosterone concentration in any samples.
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Phenotype
Table 1 shows that no anatomic changes were observed in TG mice compared with WTs. Histological examination of ventricles showed no alteration of ventricular tissue or of coronary vessels, including the perivascular area, in TG mice (not shown). Levels of ventricular AT1 and AT2 receptors and the collagen volume fraction were also unchanged in 3-month-old male TG mice (Figure 2). Using real-time polymerase chain reaction, we found no difference in the levels of expression of mRNAs coding the endothelin converting enzyme Pre-Pro-endothelin and the endothelin-1 type A receptor in TG mice ventricles compared with WTs (see Data Supplement).
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Echocardiographic evaluation was performed in separate groups of 15- and 27-week-old mice. The LV of TG mice was neither dilated nor hypertrophied, and systolic and diastolic echocardiographic parameters were similar in TG and WT mice (Table 1). At 36 weeks, LV function was also normal (not shown). Figure 3A shows that AS overexpression did not alter L-type calcium current, ICa,L, of isolated cardiac myocytes under either basal conditions or maximal ß-stimulation (isoproterenol 10–7 mol/L). Similarly, AS overexpression did not alter the characteristics of the time-dependent and -independent components of the transient outward potassium channel current, Ito1 (Figure 3B) and Isus, respectively (Figure 3C). T-type calcium current was absent in ventricular myocytes from both WT and TG mice (see Data Supplement).
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Using the perfused isolated heart, LV function in unstimulated WT and TG hearts was found to be similar, with an LV developed pressure of 73.8±2.4 versus 78.5±3.6 mm Hg, as was the sensitivity to Cao measured in hearts paced at 650 bpm (Figure 4), kinetics of contraction and relaxation (dP/dtmax and dP/dtmin normalized to LV developed pressure, time to peak tension, and relaxation half-time) (not shown). Interestingly, coronary flow was reduced by 55% in TG hearts compared with WTs (36.7±3.5 versus 81.1±14.7 mL · min–1 · g–1, respectively; P<0.05) at Cao 1.8 mmol/L.
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Coronary Function
Coronary function was studied by use of a constant-flow isolated perfused heart setup.21 Infusion of acetylcholine in the perfusion line induced a decrease in coronary resistance, expressed here in percent change of coronary perfusion pressure (CPP) relative to baseline values in WT mice (Figure 5A). The vasodilatory response was observed at 10–6 mol/L acetylcholine and was greater for higher acetylcholine concentrations (maximal decrease, 28.8±3.6 mm Hg at 10–4 mol/L acetylcholine). In contrast, responses to acetylcholine were almost abolished in TG mice, because 10–4 mol/L acetylcholine did not induce a significant decrease in CPP (Figure 5A). Similarly, coronary responses to bradykinin were decreased by 60% in TG compared with WT mice (Figure 5B). The maximal response to sodium nitroprusside was also decreased by 75% in TG hearts, indicating that the defect was endothelium independent (Figure 5C).
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Discussion |
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This work shows that cardiac-specific AS overexpression induces a slight increase in the aldosterone concentration in cardiac tissue and a major coronary vascular dysfunction in male mice, without altering cardiac structure and function.
In hearts of TG mice, we observed an important induction of AS mRNA (100 times), a moderate increase in AS protein (4 times), and a slight increase (of 1.7-fold) in aldosterone concentration compared with WT mice. This suggests that AS synthesis is controlled by mechanisms working downstream from the transcription of AS gene. It is noteworthy that this modest increase reflects the change in aldosterone content of whole homogenized hearts and is likely to underestimate the actual increase in aldosterone concentration within or in the close vicinity of cardiac myocytes, where the AS gene has been targeted.
One major finding is the marked alteration of coronary vascular responsiveness to acetylcholine and bradykinin observed at 15 weeks. To date, it is unknown whether this coronary dysfunction was present at birth or whether it developed progressively after birth. However, the well-described -MHC expression pattern in heart suggests that the AS overexpression, and presumably the cardiac overproduction of aldosterone, began early in the life of the TG mouse. TG mice had a normal postnatal development, and no postnatal mortality was observed. These observations indicate that the coronary alteration is not life threatening under physiological/basal conditions. Conversely, this silent coronary dysfunction might have important consequences if cardiac work were suddenly to change. Moreover, these results may have an important pathophysiological significance. Several studies have demonstrated an increased production of cardiac aldosterone in pathological states. This was demonstrated for the first time in a rat model of MI,10 but the situation in the human species is more confused. It is generally accepted that aldosterone production in the normal human heart is very low. However, several observations in patients with HF are in favor of a strongly increased production of aldosterone within the diseased heart14,15 (review by White23). Remarkably, our results demonstrate that a slight elevation of aldosterone synthesis is able to seriously impair coronary reserve. It is also possible that the long-term cardiac impregnation with elevated aldosterone concentrations is a crucial factor. In this respect, it is worth noting that long-lasting yet moderately increased aldosterone concentrations are typical features of human chronic cardiac diseases, in which the neurohormonal stimulation may last for months.24
Interestingly, the AS overexpression did not alter the cardiac phenotype. There was no cardiac hypertrophy or cardiac fibrosis, probably related to the modest increase of aldosterone concentration in heart and to the absence of hypertension in this model. Cardiac structure and parameters of LV contraction and relaxation, evaluated both in vivo and ex vivo, were unaltered in TG mice of any age. In addition, previous studies have demonstrated an increased L-type Ca2+ current and a decreased transient outward K+ current after 1 to 2 days of incubation of rat cardiomyocytes with high (100 nmol/L) concentrations of aldosterone.25,26 These currents were not different in ventricular myocytes from TG and WT mice, suggesting either a dose-dependent effect or different mechanisms. Finally, the absence of cardiac hypertrophy and fibrosis indicated no perturbing effect of the -MHC promoter.
This study showed that locally produced aldosterone alters coronary vascular function. It is established that aldosterone has effects on vascular reactivity, but the mechanisms are not well understood (for review, see Struthers and MacDonald).27 Most results have been obtained after chronic aldosterone blockade by spironolactone or eplerenone. In patients with HF, spironolactone improved acetylcholine-mediated endothelium-dependent vasodilation and increased nitric oxide bioactivity.28 The causative role of oxidative stress in the aldosterone-mediated vascular alterations is strongly suggested by the protective action of either spironolactone or antioxidants in either coronary7 or peripheral29,30 vessels. As demonstrated by Bauersachs et al,29 the addition of spironolactone to ACE inhibition in rats with HF results in improvements in endothelial vasomotor dysfunction that can be attributed to the normalization of nitric oxide–mediated relaxation through the beneficial modulation of nitric oxide balance and superoxide anion formation. Similarly, in rabbits fed a proatherosclerotic diet, treatment with spironolactone normalized superoxide formation and improved endothelial function.31 The mechanism for the coronary dysfunction observed in TG mice is as yet unknown. Aldosterone stimulates the production of endothelin-1 in heart.32 The expression of mRNAs coding the main components of the endothelin system were not changed in TG mice, suggesting that endothelin is probably not involved in the observed abnormality in coronary vasomotor reactivity. Because the effect of exogenous nitric oxide (nitroprusside) was also blunted in TG animals, it is possible that the alteration may involve vascular smooth muscle cells.
The suggested interactions between aldosterone-synthesizing myocytes and other cell types require further study. The present model of cardiac-specific aldosteronism has distinct features compared with the well-known model of systemic aldosteronism with added salt.4,5 In the latter, the high plasma aldosterone level and the still ambiguous effect of sodium chloride result in major damage to cardiac cells and fibrosis. In contrast, cardiac fibrosis did not develop in our TG model, most likely because the increase in the cardiac concentration of aldosterone was less marked than in the aldosterone-salt model. Conversely, this mouse model demonstrated a specific effect on coronary vascular function that has not, to date, been described by aldosterone-salt challenge. Therefore, our results indicate that coronary arteries may be a target for aldosterone. This finding extends previous observations obtained from the rat aldosterone-salt model, in which fibrinoid necrosis and the presence of inflammatory cells surrounding coronary arteries have been demonstrated.33 More recently, several laboratories have shown a pericoronary inflammatory phenotype that appears early in the aldosterone-salt–treated rats.6–8,34 Preliminary results indicate that there was no inflammatory cell proliferation around coronary arteries of TG mice hearts, probably because of the slight increase of cardiac aldosterone. Again, the present mouse model, in which plasma aldosterone was not elevated, reveals aldosterone-induced alterations whose origin is cardiac-specific.
The present study provides the first evidence that locally produced aldosterone alters coronary vascular function. Because the pathophysiological relevance of cardiac aldosterone synthesis has been questioned, it is important to underscore that this work demonstrates a novel deleterious effect of cardiac aldosterone. Moreover, it opens new perspectives by suggesting that at levels below those that induce cardiac fibrosis, locally produced aldosterone may have discrete effects that may facilitate the progression toward disease. And finally, because it induces a coronary dysfunction at levels in the range of those reached in clinical situations, it may be hypothesized that the beneficial effects of antialdosterone treatment in cardiovascular diseases such as congestive HF may be in part a result of protection against aldosterone-induced alterations of coronary function. This point deserves further investigation.
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Acknowledgments |
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This work was supported by Pharmacia France (grant 92036-4), INSERM, CNRS, and the Fondation de France. Dr Garnier was a recipient of a Pharmacia fellowship grant. The authors thank Stephane Cailmail, Francoise Marotte, Philippe Mateo, Patricia Oliviero, and Estelle Robidel for expert technical assistance; Dr Sylvie Salenave for hemodynamic measurements; Drs Jeffrey Robbins and Thierry Pedrazzini for the gift of MHC promoter; Pr Celso Gomez-Sanchez for the gift of anti-AS antibody; Dr Leigh Pascoe for the gift of adrenoreductase; and Prs Alessandro Capponi and Pierre Corvol and Drs Lydie Rappaport and Jane-Lise Samuel for helpful discussions.
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Footnotes |
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*The first 2 authors contributed equally to this work.
The online-only Data Supplement is available with this article at http://www.circulationaha.org.
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