Abstract 3574: Heart Failure Etiology and Nucleocytoplasmic Transport
Introduction: The role of nucleus in the development of heart failure (HF) is unknown, so the objectives of this study were to analyze the effect of HF on the bidirectional nucleocytoplasmic transport (NCT).
Hypothesis: We assessed the hypothesis that NCT may be altered in HF.
Methods: A total of 53 human samples from ischemic (ICM, n=31) and dilated (DCM, n=16) patients undergoing heart transplant, and control donors (CNT, n=6) were analyzed by western blot. Sub-cellular distribution of proteins and nuclear pore complex (NPC) were analyzed by fluorescence and electron microscopy.
Results: When we compared nucleocytoplasmic protein levels between HF and CNT hearts, we obtained that the four molecules (IMP- μ3, IMP- α2, EXP-1, and EXP-4) were significantly increased in pathological samples (264±93 vs. 100±12 au, p<0.0001; 163±43 vs. 100±30 au, p=0.002; 293±130 vs. 100±24 au, p<0.0001; 169±69 vs. 100±25 au, p=0.001, respectively). Then, when we compared protein levels according to etiology of HF, ICM hearts showed higher levels of IMP-β3 (250±89 vs. 100±12 au, p<0.0001), IMP-α2 (169±41 vs. 100±30 au, p=0.001), EXP-1 (278±137 vs. 100±24 au, p=0.007), and EXP-4 (181±68 vs. 100±25 au, p=0.014) than those in the CNT group. Furthermore, DCM hearts showed significant differences for IMP-β3 (292±95 vs. 100±12 au, p=0.0001), IMP-α2 (152±95 vs. 100±30 au, p=0.030) and EXP-1 (328±109 vs. 100±24 au, p<0.0001), compared to CNT group. There were not any significant differences in nuclear protein levels between the two etiologies of HF. Finally, we obtained that RanGAP1 and RaGAP1u were significantly increased according to etiology of HF: ICM (176±74 vs. 100±33 au, p=0.009; 151±72 vs. 100±25 au, p=0.009) and DCM (141±39 vs. 100±33 au, p=0.042; 150±48 vs. 100±25 au, p=0.003) compared to CNT hearts. But there were no differences for RanBP1. Furthermore, pathological hearts showed differences in protein distribution and higher NPC density compared to CNT.
Conclusions: This study shows important alterations in NCT in patients with HF, such as higher levels and different distribution of importins, exportins and Ran regulators in ischemic and dilated human hearts. This fact may be closely related with the cardiomyocyte capability of repair in heart failure.