期刊
CARDIOVASCULAR RESEARCH
卷 105, 期 1, 页码 31-43出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvu218
关键词
Myocytes; Hypertrophy; Myocardial infarction; Signal transduction; Nuclear transport
资金
- British Royal Society
- British Heart Foundation (BHF)
- Wellcome Trust Value in People Award
- Hungarian Scientific Research Fund
- National Development Agency
- NC3Rs and Rosetree's Trust
- Wellcome Trust [WTN092852]
- BHF [FS/11/67/28954]
- MRC [G0500373] Funding Source: UKRI
- British Heart Foundation [SP/09/007/27920, FS/11/67/28954] Funding Source: researchfish
- Medical Research Council [G0500373] Funding Source: researchfish
Aims During cardiac hypertrophy, cardiomyocytes (CMs) increase in the size and expression of cytoskeletal proteins while reactivating a foetal gene programme. The process is proposed to be dependent on increased nuclear export and, since nuclear pore trafficking has limited capacity, a linked decrease in import. Our objective was to investigate the role of nuclear import and export in control of hypertrophy in rat and human heart failure (HF). Methods and results In myocardial tissue and isolated CMs from patients with dilated cardiomyopathy, nuclear size was increased; Nucleoporin p62, cytoplasmic RanBP1, and nuclear translocation of importins (alpha and beta) were decreased while Exportin-1 was increased. CM from a rat HF model 16 weeks after myocardial infarction (MI) reproduced these nuclear changes. Nuclear import, determined by the rate of uptake of nuclear localization sequence (NLS)-tagged fluorescent substrate, was also decreased and this change was observed from 4 weeks after MI, before HF has developed. Treatment of isolated rat CMs with phenylephrine (PE) for 48 h produced similar cell and nuclear size increases, nuclear import and export protein rearrangement, and NLS substrate uptake decrease through p38 MAPK and HDAC-dependent pathways. The change in NLS substrate uptake occurred within 15 min of PE exposure. Inhibition of nuclear export with leptomycin B reversed established nuclear changes in PE-treated rat CMs and decreased NLS substrate uptake and cell/nuclear size in human CMs. Conclusions Nuclear transport changes related to increased export and decreased import are an early event in hypertrophic development. Hypertrophy can be prevented, or even reversed, by targeting import/export, which may open new therapeutic opportunities.
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