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Oligomeric TTR V30M aggregates compromise cell viability, erythropoietin gene expression and promoter activity in the human hepatoma cell line Hep3B

2015-06-19Journal article Restricted access
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dc.contributor.authorMoreira, Luciana V.
dc.contributor.authorBeirão, João M.
dc.contributor.authorBeirão, Idalina
dc.contributor.authorCosta, Paulo P.
dc.date.accessioned2016-02-15T12:25:46Z
dc.date.available2016-02-15T12:25:46Z
dc.date.issued2015-06-19
dc.description.abstractFamilial amyloidotic polyneuropathy, ATTRV30M (p. TTRV50M) amyloidosis, is a neurodegenerative disease characterized by systemic extracellular amyloid deposition of a mutant transthyretin, TTR V30M. Anemia, with low erythropoietin (EPO) levels and spared kidney function, affects about 25% of symptomatic patients, suggesting a blockage of EPO-producing cells. Early non-fibrillar TTR aggregates are highly cytotoxic, inducing oxidative stress, the expression of apoptosis-related molecules and secretion of pro-inflammatory cytokines, factors capable of inhibiting EPO production. Low EPO levels in these patients are not related to renal amyloid deposition or the presence of circulating TTR V30M. However, the role of early non-fibrillar TTR aggregates remains unexplored. We used the EPO producing Hep3B human hepatoma cell line to study the effect of TTR oligomeric aggregates on EPO expression. Hep3B cells were incubated with soluble and oligomeric TTR V30M, and cell proliferation as well as caspase 3/7 activation was evaluated. Relative quantification of EPO mRNA transcripts was performed by real-time PCR. Significant reductions in cell viability (13 ± 7.3%) and activation of caspases 3/7 were seen after 24 h in the presence of oligomeric TTR V30M. Also, EPO expression was significantly reduced (50 ± 2.8%), in normoxic conditions. A reporter assay was constructed with a PCR fragment of the EPO promoter linked to the luciferase gene to evaluate the role of transcription factors targeting the promoter. A significant reduction of EPO promoter activity (53 ± 6.5%) was observed in transfected cells exposed to TTR oligomers. Our results show that oligomeric TTR V30M reduces EPO expression, at least in part through inhibition of promoter activity.pt_PT
dc.description.sponsorshipLVM beneficiou de uma bolsa da FCTpt_PT
dc.identifier.citationAmyloid. 2015;22(2):93-9. doi: 10.3109/13506129.2015.1007497. Epub 2015 Jun 19.pt_PT
dc.identifier.doi10.3109/13506129.2015.1007497pt_PT
dc.identifier.issn1350-6129
dc.identifier.urihttp://hdl.handle.net/10400.18/3294
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherInforma Healthcarept_PT
dc.relation.publisherversionwww.tandfonline.com/doi/full/10.3109/13506129.2015.1007497pt_PT
dc.subjectHereditary Amyloidosispt_PT
dc.subjectATTR Amyloidosispt_PT
dc.subjectTTR V30Mpt_PT
dc.subjectErythropoietinpt_PT
dc.subjectAnemiapt_PT
dc.subjectMolecular Biologypt_PT
dc.subjectMolecular Medicinept_PT
dc.subjectEPO expressionpt_PT
dc.subjectEPO promoterpt_PT
dc.subjectFamilial Amyloid Polyneuropathypt_PT
dc.subjectTransthyretinpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectDeterminantes da Saúde e da Doençapt_PT
dc.titleOligomeric TTR V30M aggregates compromise cell viability, erythropoietin gene expression and promoter activity in the human hepatoma cell line Hep3Bpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage99pt_PT
oaire.citation.startPage93pt_PT
oaire.citation.titleAmyloid - The Journal of Protein Folding Disorderspt_PT
oaire.citation.volume22(2)pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT

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