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Exercise training and PI3K?-induced electrical remodeling is independent of cellular hypertrophy and Akt signaling.

ABSTRACT: In contrast with pathological hypertrophy, exercise-induced physiological hypertrophy is not associated with electrical abnormalities or increased arrhythmia risk. Recent studies have shown that increased cardiac-specific expression of phosphoinositide-3-kinase-? (PI3K?), the key mediator of physiological hypertrophy, results in transcriptional upregulation of ion channel subunits in parallel with the increase in myocyte size (cellular hypertrophy) and the maintenance of myocardial excitability. The experiments here were undertaken to test the hypothesis that Akt1, which underlies PI3K?-induced cellular hypertrophy, mediates the effects of augmented PI3K? signaling on the transcriptional regulation of cardiac ion channels. In contrast to wild-type animals, chronic exercise (swim) training of mice (Akt1(-/-)) lacking Akt1 did not result in ventricular myocyte hypertrophy. Ventricular K(+) current amplitudes and the expression of K(+) channel subunits, however, were increased markedly in Akt1(-/-) animals with exercise training. Expression of the transcripts encoding inward (Na(+) and Ca(2+)) channel subunits were also increased in Akt1(-/-) ventricles following swim training. Additional experiments in a transgenic mouse model of inducible cardiac-specific expression of constitutively active PI3K? (icaPI3K?) revealed that short-term activation of PI3K? signaling in the myocardium also led to the transcriptional upregulation of ion channel subunits. Inhibition of cardiac Akt activation with triciribine in this (inducible caPI3K? expression) model did not prevent the upregulation of myocardial ion channel subunits. These combined observations demonstrate that chronic exercise training and enhanced PI3K? expression/activity result in transcriptional upregulation of myocardial ion channel subunits independent of cellular hypertrophy and Akt signaling.

SUBMITTER: Yang KC

PROVIDER: S-EPMC3432661 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Exercise training and PI3Kα-induced electrical remodeling is independent of cellular hypertrophy and Akt signaling.

Yang Kai-Chien KC Tseng Yi-Tang YT Nerbonne Jeanne M JM

Journal of molecular and cellular cardiology 20120721 4

In contrast with pathological hypertrophy, exercise-induced physiological hypertrophy is not associated with electrical abnormalities or increased arrhythmia risk. Recent studies have shown that increased cardiac-specific expression of phosphoinositide-3-kinase-α (PI3Kα), the key mediator of physiological hypertrophy, results in transcriptional upregulation of ion channel subunits in parallel with the increase in myocyte size (cellular hypertrophy) and the maintenance of myocardial excitability. ...[more]

PMID: 22824041

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Project description:The perturbation of myocardial transcriptome homeostasis is the hallmark of pathological hypertrophy, underlying the maladaptive myocardial remodeling secondary to pathological stresses. Classic and novel therapeutics that provide beneficial effects against pathological remodeling likely impact myocardial transcriptome architecture, including miRNA and mRNA expression profiles. Microarray and PCR-based technologies, although employed extensively, cannot provide adequate sequence coverage or quantitative accuracy to test this hypothesis directly. The goal of this study was to develop and exploit next-generation sequencing approaches for comprehensive and quantitative analyses of myocardial miRNAs and mRNAs to test the hypothesis that augmented phosphoinositide-3-kinase-p110α (PI3Kα) signaling in the setting of pathological hypertrophy provides beneficial effects through remodeling of the myocardial transcriptome signature. In these studies, a molecular and bioinformatic pipeline permitting comprehensive analysis and quantification of myocardial miRNA and mRNA expression with next-generation sequencing was developed and the impact of enhanced PI3Kα signaling on the myocardial transcriptome signature of pressure overload-induced pathological hypertrophy was explored. These analyses identified multiple miRNAs and mRNAs that were abnormally expressed in pathological hypertrophy and partially or completely normalized with increased PI3Kα signaling. Additionally, several novel miRNAs potentially linked to remodeling in cardiac hypertrophy were identified. Additional experiments revealed that increased PI3Kα signaling reduces cardiac fibrosis in pathological hypertrophy through modulating TGF-β signaling and miR-21 expression. In conclusion, using the approach of combined miRNA and mRNA sequencing, we identify the protective transcriptome signature of enhanced PI3Kα signaling in the context of pathological hypertrophy, and demonstrate the regulation of TGF-β/miR-21 by which enhanced PI3Kα signaling protects against cardiac fibrosis.

Dataset Information

Exercise training and PI3K?-induced electrical remodeling is independent of cellular hypertrophy and Akt signaling.

Publications

Exercise training and PI3Kα-induced electrical remodeling is independent of cellular hypertrophy and Akt signaling.

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