RGD Reference Report - Sodium-hydrogen exchange inhibition attenuates glycoside-induced hypertrophy in rat ventricular myocytes. - Rat Genome Database

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Sodium-hydrogen exchange inhibition attenuates glycoside-induced hypertrophy in rat ventricular myocytes.

Authors: Gan, XT  Gong, XQ  Xue, J  Haist, JV  Bai, D  Karmazyn, M 
Citation: Gan XT, etal., Cardiovasc Res. 2010 Jan 1;85(1):79-89. Epub .
RGD ID: 6771333
Pubmed: PMID:19687166   (View Abstract at PubMed)
DOI: DOI:10.1093/cvr/cvp283   (Journal Full-text)

AIMS: Cardiac glycosides induce cardiomyocyte hypertrophy via yet to be defined mechanisms. These hypertrophic effects are likely related to changes in intracellular signalling secondary to Na(+)-K(+) ATPase (NKA) inhibition which would produce elevations in intracellular sodium concentrations. Sodium-hydrogen exchanger isoform 1 (NHE-1) also contributes to intracellular sodium regulation. Accordingly, we determined the contribution of NHE-1 to cardiac glycoside-induced hypertrophy. METHODS AND RESULTS: The majority of the experiments were performed on cultured neonatal rat ventricular myocytes exposed to either ouabain (100 microM) or digoxin (40 microM) for 24 h, although additional experiments were also done using adult left ventricular myocytes with 30 microM of either glycoside. Both glycosides increased cell surface area by 30% and atrial natriuretic peptide gene expression by two- to three-fold (P < 0.05 for both). These effects were associated with a significant reduction in the expression of two NKA isoforms, alpha(2) and alpha(3), whereas the alpha(1) isoform was unaffected. Conversely, both glycosides increased NHE-1 expression in cardiomyocytes by approximately two-fold and significantly increased intracellular sodium concentrations by more than 60% (P < 0.05). Both ouabain and digoxin were also found to significantly increase phosphorylation of mitogen-activated protein kinases. All these effect were prevented when identical experiments were carried out in the presence of the NHE-1 inhibitors EMD 87580 or AVE 4890. Identical results were obtained using adult myocytes, although this was associated with downregulation of all three NKA isoforms. Glycoside-induced increase in cell shortening or intracellular Ca(2+) transients was not significantly affected by NHE-1 inhibition. CONCLUSION: When taken together, these studies show that NHE-1 inhibition attenuates the hypertrophic effect of cardiac glycosides without affecting inotropic parameters and suggest a possible approach to limiting glycoside-induced hypertrophic responses while preserving therapeutic, i.e. inotropic, actions.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of cell growth  IMP 6771333 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Slc9a1  (solute carrier family 9 member A1)


Additional Information