Influence of heart failure on nucleocytoplasmic transport in human cardiomyocytes.
OBJECTIVE
The role of the cell nucleus in the development of heart failure (HF) is unknown, so the objectives of this study were to analyse the effect of HF on nucleocytoplasmic transport and density of the nuclear pore complex (NPC).


RESULTS
A total of 51 human heart samples from ischaemic (ICM, n = 30) and dilated (DCM, n = 16) patients undergoing heart transplantation and control donors (CNT, n = 5) were analysed by western blotting. Subcellular distribution of proteins and NPC were analysed by fluorescence and electron microscopy, respectively. When we compared nucleocytoplasmic machinery protein levels according to aetiology of HF, ICM showed higher levels of importins [(IMP-beta3) (150%, P < 0.0001), IMP-alpha2 (69%, P = 0.001)] and exportins [EXP-1 (178%, P < 0.0001), EXP-4 (81%, P = 0.006)] than those of the CNT group. Furthermore, DCM also showed significant differences for IMP-beta3 (192%, P < 0.0001), IMP-alpha2 (52%, P = 0.025), and EXP-1 (228%, P < 0.0001). RanGTPase-activating proteins (RanGAP1 and RaGAP1u) were increased in ICM (76%, P = 0.005; 51%, P = 0.012) and DCM (41%, P = 0.042; 50%, P = 0.029). Furthermore, subcellular distribution of nucleocytoplasmic machinery was not altered in pathological hearts. Finally, nucleoporin (Nup) p62 was increased in ICM (80%) and DCM (109%) (P < 0.001 and P = 0.024). Nuclear pore density was comparable in pathological and CNT hearts, and ICM showed a low diameter (P = 0.005) and different structural configuration of NPC.


CONCLUSIONS
This study shows the effect of HF on nucleocytoplasmic trafficking machinery, evidenced by higher levels of importins, exportins, Ran regulators and Nup p62 in ischaemic and dilated human hearts than those in the controls, with NPCs acquiring a different configuration and morphology in ICM.
Cortés
Raquel
R
Cardiocirculatory Unit, Research Center, Hospital Universitario La Fe, Valencia, Spain.
Roselló-Lletí
Esther
E
Rivera
Miguel
M
Martínez-Dolz
Luis
L
Salvador
Antonio
A
Azorín
Inmaculada
I
Portolés
Manuel
M
D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000328:Adult; D000368:Aged; D002467:Cell Nucleus / Q000378:metabolism*; D005260:Female; D020690:GTPase-Activating Proteins / Q000032:analysis; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D022022:Nuclear Pore / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D028961:beta Karyopherins / Q000032:analysis
D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; C107940:IPO5 protein, human; C092317:RANGAP1 protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D028961:beta Karyopherins