title: Nuclear pore rearrangements and nuclear trafficking in cardiomyocytes from rat and human failing hearts.
abstract: OBJECTIVE
  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).
  
  
  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 (α and β) 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.
authors.affiliation: NHLI, Imperial College, London, UK m.chahine@imperial.ac.uk mirnachahine01@gmail.com.
authors.forename: Mirna N
authors.initials: MN
authors.lastname: Chahine
authors.affiliation: NHLI, Imperial College, London, UK.
authors.forename: Maxime
authors.initials: M
authors.lastname: Mioulane
authors.affiliation: NHLI, Imperial College, London, UK.
authors.forename: Markus B
authors.initials: MB
authors.lastname: Sikkel
authors.affiliation: NHLI, Imperial College, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Gara
authors.affiliation: Muscle Research Unit, Bosch Institute, The University of Sydney, Sydney, Australia.
authors.forename: Cristobal G
authors.initials: CG
authors.lastname: Dos Remedios
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Grant N
authors.initials: GN
authors.lastname: Pierce
authors.affiliation: NHLI, Imperial College, London, UK NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Lyon
authors.affiliation: NHLI, Imperial College, London, UK.
authors.forename: Gábor
authors.initials: G
authors.lastname: Földes
authors.affiliation: NHLI, Imperial College, London, UK.
authors.forename: Sian E
authors.initials: SE
authors.lastname: Harding
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D019913:Nuclear Localization Signals / Q000378:metabolism; D022022:Nuclear Pore / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019913:Nuclear Localization Signals; D048051:p38 Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases
keywords: Hypertrophy; Myocardial infarction; Myocytes; Nuclear transport; Signal transduction