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Nuclear pore rearrangements and nuclear trafficking in cardiomyocytes from rat and human failing hearts.

Authors: Chahine, MN  Mioulane, M  Sikkel, MB  O'Gara, P  Dos Remedios, CG  Pierce, GN  Lyon, AR  Foldes, G  Harding, SE 
Citation: Chahine MN, etal., Cardiovasc Res. 2015 Jan 1;105(1):31-43. doi: 10.1093/cvr/cvu218. Epub 2014 Oct 23.
Pubmed: (View Article at PubMed) PMID:25341891
DOI: Full-text: DOI:10.1093/cvr/cvu218

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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CRRD Object Information
CRRD ID: 9835001
Created: 2015-03-11
Species: All species
Last Modified: 2015-03-11
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.