Abstract

Studies using pharmacological and genetic approaches have shown that increased activity/expression of the Na+/H+ exchanger isoform 1 (NHE1) play a critical role in the pathogenesis of cardiac hypertrophy. Despite the importance of NHE1 in cardiac hypertrophy, severe cerebrovascular side effects were associated with the use of NHE1 inhibitors when administered to patients with myocardial infarctions. p90 ribosomal S6 Kinase (RSK), a downstream regulator of the mitogen-activated protein kinase pathway, has also been implicated in cardiac hypertrophy. We hypothesized that RSK plays a role in the NHE1 induced cardiomyocyte hypertrophic response. Infection of H9c2 cardiomyoblasts with the active form of the NHE1 adenovirus induced hypertrophy and was associated with an increase in the phosphorylation of RSK (P<0.05). Parameters of hypertrophy such as cell area, protein content and atrial natriuretic mRNA expression were significantly reduced in H9c2 cardiomyoblasts infected with active NHE1 in the presence of dominant negative RSK (DN-RSK) (P<0.05). These results confirm that NHE1 lies upstream of RSK. Increased phosphorylation and activation of GATA4 at Ser261 was correlated with increased RSK phosphorylation. This increase was reversed upon inhibition of RSK or NHE1. These findings demonstrate for the first time that the NHE1 mediated hypertrophy is accounted for by increased activation and phosphorylation of RSK, which subsequently increased the phosphorylation of GATA4; eventually activating fetal gene transcriptional machinery.

Highlights

  • Cardiovascular diseases (CVDs) remain one of the leading causes of death worldwide despite the advances in treatment [1]

  • No reports have directly investigated whether expression of active Na+/H+ exchanger isoform 1 (NHE1) induces ribosomal S6 Kinase (RSK) and how RSK contributes to the NHE1-mediated hypertrophic response in cardiomyocytes

  • Previous reports have demonstrated that the anti-hypertrophic effect of NHE1 inhibition in PE treated neonatal rat ventricular cardiomyocytes (NRVMs) was found to be associated with prevention of mitogen activated protein kinase (MAPKs) activation [50]

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Summary

Introduction

Cardiovascular diseases (CVDs) remain one of the leading causes of death worldwide despite the advances in treatment [1]. Cardiomyocyte hypertrophy (CH), a condition that occurs in response to mechanical load and neurohormonal stimulation, is characterized by an increase in cardiomyocyte size, enhanced protein synthesis and the reactivation of the fetal gene program [2]. Pathological CH results in left ventricular dysfunction and heart failure if left unresolved [3]. Neurohormonal stimulation mediated by α-adrenergic agonists including phenylephrine. Cardiomyocyte Hypertrophy and p90 Ribosomal S6 Kinase

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