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

Abstract

AimsDuring 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 resultsIn 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.ConclusionsNuclear 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.

High and Low Salt Intake during Pregnancy: Impact on Cardiac and Renal Structure in Newborns

“…We evaluated the nuclear diameter of cardiomyocytes because of the immaturity in newborns, which makes it difficult to define the limits of the cells. Previous studies validated this hypertrophy assessment method [28]. The present study demonstrated that the myocardial structural alterations in adult offspring of dams fed an HS diet described by Alves-Rodrigues et al [1] are already present at birth.…”

Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

“…Indeed, it was shown that the nuclear pore proteins Nup62, Nup153, and Nup214 are phosphorylated by p38 (or ERK), and this phosphorylation inhibits the global nuclear protein shuttling initiated by viruses that affect the heart such as the encephalomyocarditis virus [44]. A similar effect was detected in cardiomyocytes of failing hearts in rats and humans, where p38α/β phosphorylation mediates the rearrangement of nuclear pores, leading to a decreased uptake of nuclear localization signal (NLS)-containing proteins [45]. As for karyopherins, it was shown that p38α/β regulate the expression of the beta-like importins (Imp) Imp7 and Imp8 [46], which are important for the nuclear translocation of various signaling proteins.…”

Nuclear envelope and genome interactions in cell fate

“…For instance, Nup50, a dynamic Nup, is highly expressed in the mammalian neural tube and the testis, particularly in the male germ cells ( Trichet et al, 1999 ; Smitherman et al, 2000 ), while Nup45 exhibits variable expression in select mouse and rat cell lines ( Hu and Gerace, 1998 ). Several Nups have been reported to change expression during cardiomyocyte differentiation ( Perez-Terzic et al, 2003 ), as well as in response to cardiac hypertrophy ( Chahine et al, 2015 ). Publically available genome wide expression studies in various cell types and organs also readily show differential expression of Nups.…”