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Open Access Research article

Resistance to cardiomyocyte hypertrophy in ae3 −/− mice, deficient in the AE3 Cl/HCO3 exchanger

Daniel Sowah1, Brittany F Brown1, Anita Quon1, Bernardo V Alvarez2 and Joseph R Casey1*

Author Affiliations

1 Department of Biochemistry and Membrane Protein Disease Research Group, University of Alberta, Edmonton T6G 2H7, Canada

2 Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Medicas, Universidad Nacional de La Plata, La Plata, Argentina

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BMC Cardiovascular Disorders 2014, 14:89  doi:10.1186/1471-2261-14-89

Published: 21 July 2014

Abstract

Background

Cardiac hypertrophy is central to the etiology of heart failure. Understanding the molecular pathways promoting cardiac hypertrophy may identify new targets for therapeutic intervention. Sodium-proton exchanger (NHE1) activity and expression levels in the heart are elevated in many models of hypertrophy through protein kinase C (PKC)/MAPK/ERK/p90RSK pathway stimulation. Sustained NHE1 activity, however, requires an acid-loading pathway. Evidence suggests that the Cl/HCO3 exchanger, AE3, provides this acid load. Here we explored the role of AE3 in the hypertrophic growth cascade of cardiomyocytes.

Methods

AE3-deficient (ae3−/−) mice were compared to wildtype (WT) littermates to examine the role of AE3 protein in the development of cardiomyocyte hypertrophy. Mouse hearts were assessed by echocardiography. As well, responses of cultured cardiomyocytes to hypertrophic stimuli were measured. pH regulation capacity of ae3−/− and WT cardiomyocytes was assessed in cultured cells loaded with the pH-sensitive dye, BCECF-AM.

Results

ae3−/− mice were indistinguishable from wild type (WT) mice in terms of cardiovascular performance. Stimulation of ae3−/− cardiomyocytes with hypertrophic agonists did not increase cardiac growth or reactivate the fetal gene program. ae3−/− mice are thus protected from pro-hypertrophic stimulation. Steady state intracellular pH (pHi) in ae3−/− cardiomyocytes was not significantly different from WT, but the rate of recovery of pHi from imposed alkalosis was significantly slower in ae3−/− cardiomyocytes.

Conclusions

These data reveal the importance of AE3-mediated Cl/HCO3 exchange in cardiovascular pH regulation and the development of cardiomyocyte hypertrophy. Pharmacological antagonism of AE3 is an attractive approach in the treatment of cardiac hypertrophy.

Keywords:
AE3; Bicarbonate transport; Chloride/bicarbonate exchange; pH regulation; Cardiomyocyte hypertrophy; Heart failure