Aldosterone Increases NHE-1 Expression and Induces NHE-1-Dependent Hypertrophy in Neonatal Rat Ventricular Myocytes

Abstract

Abstract-We determined the effect of 24-hour aldosterone (100 nmol/L) treatment on hypertrophic responses in rat neonatal ventricular myocytes and the possible role of Na ϩ -H ϩ exchange isoform 1 (NHE-1). Aldosterone significantly increased cell size by 61% and expression of atrial natriuretic peptide by 2-fold. NHE-1 mRNA expression and protein abundance were significantly increased, and intracellular Na ϩ levels were elevated. Both hypertrophy and elevated Na ϩ levels were prevented by the NHE-1-specific inhibitor EMD87580 as well as the aldosterone antagonist spironolactone, although the increased NHE-1 levels were prevented only by spironolactone. Aldosterone transiently (within 5 minutes) stimulated p44/42 phosphorylation, which decreased thereafter for the remaining 24 hours, whereas p38 phosphorylation was reduced. Neither a p38 nor a p44/42 inhibitor had any effect on aldosterone-induced hypertrophy or NHE-1 regulation. Our results therefore demonstrate a direct hypertrophic effect of aldosterone on cultured myocytes, which is dependent on NHE-1 activity. (Hypertension. 2003;42:1171-1176.)Key Words: aldosterone Ⅲ sodium-proton exchange Ⅲ kinase Ⅲ rats Ⅲ hypertrophy, cardiac Ⅲ myocytes C ardiac hypertrophy represents a major component of myocardial remodeling contributing to heart failure. 1 Hypertrophy is mediated by endocrine, paracrine, and autocrine growth factors acting via complex cell-signaling processes. 2,3 Aldosterone might contribute to heart failure independently of its renal effects (reviewed in Slight et al 4 ). Aldosterone is produced in cardiac tissue, and aldosterone receptors have been identified in the cardiac cell. 5,6 The aldosterone antagonist spironolactone has been shown to reduce mortality in patients with severe heart failure, although the precise mechanism is unknown. 7 Aldosterone infusion into uninephrectomized rats produces cardiac hypertrophy, which is attenuated by the angiotensin II type 1 receptor antagonist losartan as well by 2 calcineurin inhibitors. 8 Moreover, aldosterone failed to directly produce hypertrophy in cultured neonatal rat ventricular myocytes, although a synergistic hypertrophic effect with endothelin-1 was reported. 9 The preceding 2 studies suggest an indirect cardiac hypertrophic influence of aldosterone. However, in view of the demonstration of cardiac aldosterone receptors, 5,6 we hypothesized that direct aldosterone receptor-mediated actions on the cardiac cell could be predicted and therefore, determined whether it exerts direct hypertrophic effects. We focused on the potential role of the Na ϩ -H ϩ exchanger isoform 1 (NHE-1) in this response, because inhibition of the antiporter has been shown to attenuate myocardial hypertrophy and heart failure. 10 -13 Moreover, aldosterone activates NHE-1, including that in cardiac cells, 14,15 although with respect to the latter, this occurred only after 9 days of treatment. 15 Patients with primary aldosteronism have increased erythrocyte NHE activity. 16 In the present study, we examined the direct e...

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

“…6). In contrast, p38 phosphorylation has been shown to be reduced by short-term aldosterone stimulation in NRCMs (Karmazyn et al 2003), indicating the possibility that aldosterone preconditioning attenuates the maladaptive p38 activation induced by IRI. The 27-kDa small heat-shock protein (HSP27) is a major downstream regulator of p38MAPK signaling cascades, whose phosphorylation has been shown to protect against IRI (Sanada et al 2001, Marais et al 2005.…”

c-Src–Dependent Nongenomic Signaling Responses to Aldosterone Are Increased in Vascular Myocytes From Spontaneously Hypertensive Rats

“…9,11,18,29 Besides its well-known genomic actions, aldosterone induces rapid cellular responses by activating signaling pathways independently of genomic effects. [17][18][19][20][21][22][23][24][25][26][27][28][29] The protein tyrosine kinase c-Src is abundant in the vasculature and appears to be an important signaling molecule in VSMCs. c-Src induces activation of MAPKs (p38MAPK, c-Jun NH 2 -terminal kinase, and ERK1/2), which are associated with cell growth, apoptosis, and collagen deposition.…”

“…Aldosterone induces rapid cellular responses by modulating intracellular calcium (Ca 2ϩ ) and cAMP levels, Na ϩ /H ϩ exchanger activity, and phosphorylation of signaling molecules, including protein kinase C, epidermal growth factor receptor, and mitogen-activated protein kinases (MAPKs), including c-Jun NH 2 -terminal kinase, and extracellular signal-regulated kinases (ERKs) 1/2. [17][18][19][20][21][22][23][24][25][26][27][28] We recently demonstrated that aldosterone rapidly increases activation of p38 MAPK and NAD(P)H oxidase through c-Src-dependent pathways in vascular smooth muscle cells (VSMCs). In addition, the profibrotic action of aldosterone was dependent on c-Src-regulated p38 MAPK.…”

miR-23a functions downstream of NFATc3 to regulate cardiac hypertrophy

“…These results reveal a model to understanding the molecular regulation of miRNAs in cardiac hypertrophy. (17)(18)(19)(20). We attempted to understand whether miRNAs participate in conveying their hypertrophic signals.…”