title: Functional networks of nucleocytoplasmic transport-related genes differentiate ischemic and dilated cardiomyopathies. A new therapeutic opportunity.
abstract: Heart failure provokes alterations in the expression of nucleocytoplasmic transport-related genes. To elucidate the nucleocytoplasmic transport-linked functional network underlying the two major causes of heart failure, ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), we examined global transcriptome profiles of left ventricular myocardium tissue samples from 31 patients (ICM, n = 10; DCM, n = 13) undergoing heart transplantation and control donors (CNT, n = 8) using RNA-Sequencing and GeneMANIA. Comparative profiling of ICM versus control and DCM versus control showed 1081 and 2440 differentially expressed genes, respectively (>1.29-fold; P<0.05). GeneMANIA revealed differentially regulated functional networks specific to ICM and DCM. In comparison with CNT, differential expression was seen in 9 and 12 nucleocytoplasmic transport-related genes in ICM and DCM groups, respectively. DDX3X, KPNA2, and PTK2B were related to ICM, while SMURF2, NUP153, IPO5, RANBP3, NOXA1, and RHOJ were involved in DCM pathogenesis. Furthermore, the two pathologies shared 6 altered genes: XPO1, ARL4, NFKB2, FHL3, RANBP2, and RHOU showing an identical trend in expression in both ICM and DCM. Notably, the core of the derived functional networks composed of nucleocytoplasmic transport-related genes (XPO1, RANBP2, NUP153, IPO5, KPNA2, and RANBP3) branched into several pathways with downregulated genes. Moreover, we identified genes whose expression levels correlated with left ventricular mass index and left ventricular function parameters in HF patients. Collectively, our study provides a clear distinction between the two pathologies at the transcriptome level and opens up new possibilities to search for appropriate therapeutic targets for ICM and DCM.
authors.affiliation: Cardiocirculatory Unit, Health Research Institute Hospital La Fe, Valencia, Spain.
authors.forename: María Micaela
authors.initials: MM
authors.lastname: Molina-Navarro
authors.affiliation: Sistemas Genómicos, Valencia, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Triviño
authors.affiliation: Heart Failure and Transplantation Unit, Cardiology Department, La Fe University Hospital, Valencia, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Dolz
authors.affiliation: Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Santiago de Compostela, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Lago
authors.affiliation: Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Santiago de Compostela, Spain.
authors.forename: Jose Ramón
authors.initials: JR
authors.lastname: González-Juanatey
authors.affiliation: Cardiocirculatory Unit, Health Research Institute Hospital La Fe, Valencia, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Portolés
authors.affiliation: Cardiocirculatory Unit, Health Research Institute Hospital La Fe, Valencia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Rivera
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D059467:Transcriptome; D016277:Ventricular Function, Left