Abstract 9431: Heart Failure Induces Significant Changes in the Nuclear Pore Complex of Human Cardiomyocytes

Abstract

Introduction: We have recently reported alterations in different transporters that orchestrate the nucleocytoplasmic transport, such as increased importin and exportin levels in patients diagnosed with heart failure (HF). We hypothesized whether we could also find alterations in the nuclear pore complex (NPC) structure, the gateway connecting the nucleoplasm and cytoplasm. Therefore, we quantified several representative proteins that compose the different parts of NPCs, named nucleoporins (Nup), in this syndrome. Methods: A total of 90 human heart samples from ischemic (ICM, n=45) and dilated (DCM, n=36) patients undergoing heart transplant and control donors (CNT, n=9), were analyzed (nuclear-cytoplasmic fractionation) by Western-blotting. Subcellular distribution of proteins was analyzed by immunocytochemistry, fluorescence and electron microscopy. Results: When we compared nucleoporin protein levels according to etiology, ICM showed significant higher levels of linker Nup93 (42%, p<0.0001), FG Nup153 (139%, p<0.01) and transmembrane ring Nup NDC1 (65%, p<0.0001) than those of the CNT group. Furthermore, DCM also showed significant differences for Nup93 (88%, p<0.0001), Nup153 (157%, p<0.01) and NCD1 (41%, p<0.0001). However, the nucleoporins Nup155, Nup160 and translocated promoter region (TPR) did not show significant differences. Furthermore, subcellular distribution of nucleoporins was not altered in pathological hearts, although we observed an increase in the fluorescence intensity in ICM and DCM samples of those Nup with high protein levels. Conclusions: This study shows alterations in specific proteins that compose NPC, overall those that are directly exposed to cargo undergoing transport (Nup93 and Nup153) and those that surround the core (NDC1), in hearts from patients with ICM and DCM. These changes could be accompanied by modifications in the functional dynamics through NPC and therefore our findings may be the basis for a new approach to HF management.