Mineralocorticoid Receptor Is Overexpressed in Cardiomyocytes of Patients With Congestive Heart Failure

Yoshida, Masahiro; Ma, Jun; Tomita, Tsutomu; Morikawa, Norihiro; Tanaka, Nobuyoshi; Masamura, Katsumi; Kawai, Yasuyuki; Miyamori, Isamu

doi:10.1111/j.1527-5299.2005.03722.x

Cited by 57 publications

(31 citation statements)

References 45 publications

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“…This is particularly important for the failing heart in which the mineralocorticoid receptor is overexpressed. 3 Indeed, immunohistochemical staining of the receptor was dense in the cytoplasm of the myocytes of the failing heart compared with controls. 3 Interestingly, eplerenone had a similar effect on the pump current density when administered, in vitro, to myocytes from animals not treated chronically with eplerenone.…”

Section: Discussionmentioning

confidence: 99%

“…3 Indeed, immunohistochemical staining of the receptor was dense in the cytoplasm of the myocytes of the failing heart compared with controls. 3 Interestingly, eplerenone had a similar effect on the pump current density when administered, in vitro, to myocytes from animals not treated chronically with eplerenone. Further studies will be needed to clarify the detailed mechanisms by which eplerenone activates the sodium-potassium pump.…”

Section: Discussionmentioning

confidence: 99%

“…2 Furthermore, the mineralocorticoid receptor is expressed in cardiomyocytes of patients with congestive heart failure. 3 It is known that aldosterone plays an important role in cardiac remodelling. Indeed, adverse effects of aldosterone in the cardiovascular system includes fibrosis, left ventricular hypertrophy, hypertension, congestive heart failure and sudden death due to ventricular arrhythmias.…”

Section: Introductionmentioning

confidence: 99%

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Beneficial Effect of Eplerenone on Cardiac Remodelling and Electrical Properties of the Failing Heart

Mello

2006

J Renin Angiotensin Aldosterone Syst

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Introduction. The effect of chronic administration of eplerenone on cardiac remodelling and electrical properties was investigated in the failing heart of cardiomyopathic hamsters (TO-2) at five months of age. Materials and Methods. Two-month-old hamsters were treated with eplerenone (200 mg/kg/day) administered into the chow for a period of three months. Measurements of membrane potential were performed with intracellular microelectrodes connected to a high impedance DC amplifier. The thickness of the ventricular wall as well as the area of fibrosis were measured. To investigate the influence of eplerenone on the electrogenic sodium pump myocytes were isolated from the ventricle and the pump current density was measured in voltage clamped cells using the whole cell clamp configuration. Results. The results indicated that: 1) the width of the left and right ventricular wall was significantly reduced; 2) the heart weight/body weight ratio was decreased by 38±2.4% (n=24) (p<0.05); 3) the fibrotic area in the left ventricle (LV) was reduced by 12.6±2% (n=25) (p<0.05); 4) the incidence of cardiac arrhythmias was decreased from 58±3.8% (n=20) in the control to 40±4.1% (n=20) (p<0.05) in animals treated with eplerenone. Moreover, a significant reduction in the dispersion of the QT interval was found with the drug; 5) eplerenone increased the resting potential of ventricular fibres from 64.3±1.5 mV to 73.4±1.4 mV (n=30) (p<0.05), an effect related to the activation of an electrogenic sodium pump. The conduction velocity, in longitudinal direction, was enhanced from 50±2.2 cm/s (n=10) in the controls to 59±2.4 cm/s (n=13) (p<0.05) in animals treated with eplerenone. Conclusions. Eplerenone reduces cardiac remodelling, the incidence of cardiac arrhythmias and improves impulse propagation, an effect in part related to the antifibrotic effect of the drug but also to the activation of the electrogenic sodium pump.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Beneficial Effect of Eplerenone on Cardiac Remodelling and Electrical Properties of the Failing Heart

Mello

2006

J Renin Angiotensin Aldosterone Syst

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“…6,7 Aldo and sodium load have been reported to cause inflammation and fibrosis in the cardiovascular system. 8,9 However, because the heart and the vasculature do not have enough expression of 11b-hydroxysteroid dehydrogenase type 2, 10 the precise mechanism of how Aldo binds MR and expresses its pro-inflammatory action without glucocorticoid deactivation has not yet been elucidated. Osteopontin (OPN), which is an acidic glycoprotein of B300 amino acids, was first described after it was isolated from bovine bone matrix.…”

Section: Introductionmentioning

confidence: 99%

Aldosterone-induced osteopontin gene transcription in vascular smooth muscle cells involves glucocorticoid response element

et al. 2011

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Osteopontin (OPN) is known to be one of the cytokines that is involved in the vascular inflammation caused by aldosterone (Aldo). Previous reports have shown that Aldo increases OPN transcripts, and the mechanisms for this remain to be clarified. In this study, we investigated how Aldo increases OPN transcripts in the vascular smooth muscle cells of rats. Aldosterone increased OPN transcripts time-dependently as well as dose-dependently. This increase was diminished by eplerenone, a mineralocorticoid receptor (MR) antagonist. Luciferase promoter assays showed that the OPN promoter deleted to the À1599 site retained the same promoting ability as the full-length OPN promoter when stimulated by 10 À7 M Aldo, but the promoter deleted to the À1300 site lost the promoting ability. A glucocorticoid response element (GRE) is located in that deleted region. Luciferase assays of a mutated promoter without the GRE lost the luciferase upregulation, although mutated promoters with the deletion of other consensus sites maintained the promoter activity. The binding of the Aldo-MR complex to the GRE fragment was confirmed by an electrophoretic-mobility shift assay. This is the first report showing that Aldo regulates the transcriptional levels of OPN and inflammatory responses in the vasculature through a specific GRE site in the OPN promoter region.

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“…5 RALES 6 and EPHESUS 7 have demonstrated that the addition of MR antagonists to optimal medical therapy substantially reduces the risk of both morbidity and mortality among patients with severe heart failure or acute myocardial infarction complicated by left ventricular dysfunction and heart failure. The RAAS activation in AF is similar to that in heart failure; it can therefore be hypothesized that the expression of MR in patients with AF may change.…”

Section: Introductionmentioning

confidence: 99%

Increased Expression of Mineralocorticoid Receptor and 11β‐Hydroxysteroid Dehydrogenase Type 2 in Human Atria During Atrial Fibrillation

Pei

Zhao

et al. 2010

Clinical Cardiology

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BackgroundAtrialfibrillation (AF) is associated with the activation of the renin‐angiotensin‐aldosterone system in the atria. It is not clear whether the expression of a mineralocorticoid receptor (MR), or 11β‐hydroxysteroid dehydrogenase type 2 (11βHSD2), conferring aldosterone specificity to the MR, in patients with AF is altered.HypothesisPatients with AF may be associated with increased expression of MR and 11βHSD2 in the atria.MethodsAtrial tissue samples of 25 patients with rheumatic heart valve disease undergoing a valve replacement operation were examined. A total of 13 patients had chronic persistent AF (>6 mo) and 12 patients had no history of AF. The MR and 11βHSD2 expression were analyzed at the mRNA and protein level. The localization of MR and 11βHSD2 in atrial tissue was performed using specific immunohistochemistry staining.ResultsThe results of real‐time quantitative polymerase chain reaction (PCR) showed that AF groups, in comparison with sinus rhythm, had a higher mRNA expression level of MR or 11βHSD2 (all P < 0.01). Both the MR and 11βHSD2 protein expression level in atrial tissue were also significantly increased in patients with AF compared with patients with sinus rhythm (P < 0.05 or P < 0.01). The immunohistochemical staining of MR or 11βHSD2 demonstrated that MR and 11βHSD2 predominately located in the cytoplasm of myocardial cells in the atrium and the intensity and density of immunostaining appeared to be increased in the atria of patients with AF compared to those without AF.ConclusionsIncreasing expression of MR and 11βHSD2 in the atria during AF is one of the molecular mechanisms for development of atrial interstitial fibrosis in patients with AF. These findings may have an important impact on the treatment of AF with aldosterone antagonists. Copyright © 2010 Wiley Periodicals, Inc.

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Mineralocorticoid Receptor Is Overexpressed in Cardiomyocytes of Patients With Congestive Heart Failure

Cited by 57 publications

References 45 publications

Beneficial Effect of Eplerenone on Cardiac Remodelling and Electrical Properties of the Failing Heart

Beneficial Effect of Eplerenone on Cardiac Remodelling and Electrical Properties of the Failing Heart

Aldosterone-induced osteopontin gene transcription in vascular smooth muscle cells involves glucocorticoid response element

Increased Expression of Mineralocorticoid Receptor and 11β‐Hydroxysteroid Dehydrogenase Type 2 in Human Atria During Atrial Fibrillation

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