Aldosterone directly stimulates cardiac myocyte hypertrophy

Okoshi, Marina Politi; Yan, Xinhua; Okoshi, Katashi; Nakayama, Masaaki; Schuldt, Adam J.T.; OʼConnell, Timothy D.; Simpson, Paul C.; Lorell, Beverly H.

doi:10.1016/j.cardfail.2004.03.002

Cited by 85 publications

(71 citation statements)

References 34 publications

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“…[30][31][32][33] However, the precise molecular mechanisms are not fully understood. The MR is a specific aldosterone receptor and a member of the nuclear hormone receptor superfamily.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Signaling Associates With p300/GATA4 Transcriptional Pathway During the Hypertrophic Response of Cardiomyocytes

Yoshida

Morimoto

Takaya

et al. 2010

Circ J

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Background: Aldosterone exerts its effect by binding to specific mineralocorticoid receptors (MRs). Spironolactone blocks the aldosterone system, which ameliorates heart failure in humans, but the precise molecular mechanisms of MR blockade are unclear. Methods and Results:Neonatal rat cardiomyocytes were stimulated with phenylephrine (PE), aldosterone, and/or spironolactone. The association of the MR with p300, a transcriptional coactivator of GATA4 required for hypertrophic responses, was examined. MR and p300 synergistically activated GATA4-dependent atrial natriuretic factor (ANF) promoter activities. The stimulation of cardiomyocytes with PE induced translocation of the MRs into the nuclei and markedly increased the association of MRs with p300. Compatible with the synergistic activation by the MR and p300, aldosterone further augmented the PE-induced increase in cell size and induction of ANF gene transcription. Blockade of MR activation by spironolactone inhibited the PE-induced nuclear translocation of MRs and hypertrophic responses. Conclusions:For the first time it has been demonstrated that the aldosterone/MR system associates with the p300/GATA4 transcriptional pathway during the hypertrophic response of cardiomyocytes, and may provide a mechanism of the beneficial effects of aldosterone-blocking agents in heart failure therapy in humans. (Circ J 2010; 74: 156 - 162)

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“…[30][31][32][33] However, the precise molecular mechanisms are not fully understood. The MR is a specific aldosterone receptor and a member of the nuclear hormone receptor superfamily.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Signaling Associates With p300/GATA4 Transcriptional Pathway During the Hypertrophic Response of Cardiomyocytes

Yoshida

Morimoto

Takaya

et al. 2010

Circ J

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“…Other investigators have found that aldosterone directly stimulates myocyte surface area (Okoshi et al 2004) and remodeling of myocyte membrane (Kliche et al 2006) in cultures of neonatal myocytes, an effect presumed to be mediated by MR in the myocytes. Cortisol also increases expression of atrial natriuretic peptide in cultured neonatal myocytes, and both cortisol and aldosterone potentiate the effect of phenylephrine on hypertrophy in these cultures (Lister et al 2006), also indicating an intracardiac action at MR in these cultures.…”

Section: Role Of Mr and Gr In The Heartmentioning

confidence: 94%

Cardiac corticosteroid receptors mediate the enlargement of the ovine fetal heart induced by chronic increases in maternal cortisol

Reini¹,

Dutta²,

Wood³

et al. 2008

Journal of Endocrinology

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Previous studies have demonstrated that modest, physiologically relevant increases in maternal cortisol in late gestation result in enlargement of the fetal heart. In this study, we investigated the role of mineralocorticoid receptor (MR) or glucocorticoid receptor (GR) in this enlargement. Ewes with single fetuses were randomly assigned at w120 days of gestation to one of four groups: maternal cortisol infusion (1 mg/kg per day, cortisol); maternal cortisol infusion with fetal intrapericardial infusion of the MR antagonist (MRa) potassium canrenoate (600 mg/day; cortisolCMRa); maternal cortisol infusion with fetal intrapericardial infusion of the GR antagonist (GRa) mifepristone (50 mg/day, cortisolCGRa); and maternal saline infusion (control). At w130 days of gestation, fetal heart to body weight ratio and right ventricular (RV) and left ventricular (LV) free wall thicknesses were increased in the cortisol group when compared with control group. Fetal hearts from the cortisolCMRa group weighed significantly less, with thinner LV, RV, and interventricular septum walls, when compared with the cortisol group. Fetal hearts from the cortisolCGRa group had significantly thinner RV walls than the cortisol group. Fetal arterial pressure and heart rate were not different among groups at 130 days. Picrosirius red staining of fetal hearts indicated that the increased size was not accompanied by cardiac fibrosis. These results suggest that physiologic increases in maternal cortisol in late gestation induce fetal cardiac enlargement via MR and, to a lesser extent, by GR, and indicate that the enlargement is not secondary to an increase in fetal blood pressure or an increase in fibrosis within the fetal heart.

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“…During ischemia, nongenomic aldosterone effects reduce coronary blood flow and thereby impair cardiac metabolic and contractile function (Fujita et al 2005). Aldosterone/MR can also directly stimulate hypertrophy in neonatal rat ventricular myocytes through the activation of ERK, JNK and PKCα (Okoshi et al 2004). Additionally, aldosterone via PKCε leads to a rapid but prolonged activation of Na + K + 2Cl − cotransporter and a decrease in Na + -K + -ATPase activity, which supports myocyte hypertrophy (Mihailidou et al 1998(Mihailidou et al , 2000(Mihailidou et al , 2002(Mihailidou et al , 2004).…”

Section: Endothelial Cellsmentioning

confidence: 92%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor

Ruhs

Nolze

Hübschmann

et al. 2017

Journal of Endocrinology

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The mineralocorticoid receptor (MR) belongs to the steroid hormone receptor family and classically functions as a ligand-dependent transcription factor. It is involved in water-electrolyte homeostasis and blood pressure regulation but independent from these effects also furthers inflammation, fibrosis, hypertrophy and remodeling in cardiovascular tissues. Next to genomic effects, aldosterone elicits very rapid actions within minutes that do not require transcription or translation and that occur not only in classical MR epithelial target organs like kidney and colon but also in nonepithelial tissues like heart, vasculature and adipose tissue. Most of these effects can be mediated by classical MR and its crosstalk with different signaling cascades. Near the plasma membrane, the MR seems to be associated with caveolin and striatin as well as with receptor tyrosine kinases like EGFR, PDGFR and IGF1R and G proteincoupled receptors like AT1 and GPER1, which then mediate nongenomic aldosterone effects. GPER1 has also been named a putative novel MR. There is a close interaction and functional synergism between the genomic and the nongenomic signaling so that nongenomic signaling can lead to long-term effects and support genomic actions. Therefore, understanding nongenomic aldosterone/MR effects is of potential relevance for modulating genomic aldosterone effects and may provide additional targets for intervention.

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Aldosterone directly stimulates cardiac myocyte hypertrophy

Cited by 85 publications

References 34 publications

Aldosterone Signaling Associates With p300/GATA4 Transcriptional Pathway During the Hypertrophic Response of Cardiomyocytes

Aldosterone Signaling Associates With p300/GATA4 Transcriptional Pathway During the Hypertrophic Response of Cardiomyocytes

Cardiac corticosteroid receptors mediate the enlargement of the ovine fetal heart induced by chronic increases in maternal cortisol

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor

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