Nuclear pore rearrangements and nuclear trafficking in cardiomyocytes from rat and human failing hearts. (23rd October 2014)

• Record Type: Journal Article
• Authors: Chahine, Mirna N.; Mioulane, Maxime; Sikkel, Markus B.; O'Gara, Peter; Dos Remedios, Cristobal G.; Pierce, Grant N.; Lyon, Alexander R.; Földes, Gábor; Harding, Sian E.
• Is Part Of: Cardiovascular research. Volume 105:Number 1(2015)
• Page Start: 31
• Page End: 43
• Publication Date: 2014-10-23
• Subjects: Myocytes -- Hypertrophy -- Myocardial infarction -- Signal transduction -- Nuclear transport; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvu218
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: 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 (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.