Linked Life Data

20974681

Source:http://linkedlifedata.com/resource/pubmed/id/20974681

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
Pt 24
pubmed:dateCreated
2010-12-21
pubmed:abstractText
Pathological biomechanical stresses cause cardiac hypertrophy, which is associated with QT prolongation and arrhythmias. Previous studies have demonstrated that repolarizing K(+) current densities are decreased in pressure overload-induced left ventricular hypertrophy, resulting in action potential and QT prolongation. Cardiac hypertrophy also occurs with exercise training, but this physiological hypertrophy is not associated with electrical abnormalities or increased arrhythmia risk, suggesting that repolarizing K(+) currents are upregulated, in parallel with the increase in myocyte size, to maintain normal cardiac function. To explore this hypothesis directly, electrophysiological recordings were obtained from ventricular myocytes isolated from two mouse models of physiological hypertrophy, one produced by swim-training of wild-type mice and the other by cardiac-specific expression of constitutively active phosphoinositide-3-kinase-p110? (caPI3K?). Whole-cell voltage-clamp recordings revealed that repolarizing K(+) current amplitudes were higher in ventricular myocytes isolated from swim-trained and caPI3K?, compared with wild-type, animals. The increases in K(+) current amplitudes paralleled the observed cellular hypertrophy, resulting in normalized or increased K(+) current densities. Electrocardiographic parameters, including QT intervals, as well as ventricular action potential waveforms in swim-trained animals/myocytes were indistinguishable from controls, demonstrating preserved electrical function. Additional experiments revealed that inward Ca(2+) current amplitudes/densities were also increased in caPI3K?, compared with WT, left ventricular myocytes. The expression of transcripts encoding K(+), Ca(2+) and other ion channel subunits was increased in swim-trained and caPI3K? ventricles, in parallel with the increase in myocyte size and with the global increases in total cellular RNA expression. In contrast to pathological hypertrophy, therefore, the functional expression of repolarizing K(+) (and depolarizing Ca(2+)) channels is increased with physiological hypertrophy, reflecting upregulation of the underlying ion channel subunit transcripts and resulting in increased current amplitudes and the normalization of current densities and action potential waveforms. Taken together, these results suggest that activation of PI3K? signalling preserves normal myocardial electrical functioning and could be protective against the increased risk of arrhythmias and sudden death that are prevalent in pathological cardiac hypertrophy.
pubmed:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1469-7793
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
588
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5015-32
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Homeostatic regulation of electrical excitability in physiological cardiac hypertrophy.
pubmed:affiliation
Department of Developmental Biology, Washington University Medical School, St Louis, MO 63110-1093, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural