4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification

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dc.contributor(LEDS) Lab. Dor e Sinalizaçãopt_BR
dc.contributor.authorKiyuna, Ligia A.pt_BR
dc.contributor.authorCandido, Darlan S.pt_BR
dc.contributor.authorBechara, Luiz R. G.pt_BR
dc.contributor.authorZambelli, Vanessa Olzonpt_BR
dc.date.accessioned2023-11-13T13:11:22Z-
dc.date.available2023-11-13T13:11:22Z-
dc.date.issued2023pt_BR
dc.identifier.citationKiyuna LA., Candido DS., Bechara LR.G., Zambelli VO. 4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification. Eur Heart J. 2023 Nov; ehad662. doi:10.1093/eurheartj/ehad662.pt_BR
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/5137-
dc.description.abstractBackground and Aims Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure. Methods Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets. Results 4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure. Conclusions 4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure.pt_BR
dc.format.extentehad662pt_BR
dc.language.isoEnglishpt_BR
dc.relation.ispartofEuropean Heart Journalpt_BR
dc.rightsRestricted accesspt_BR
dc.title4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modificationpt_BR
dc.typeArticlept_BR
dc.identifier.doi10.1093/eurheartj/ehad662pt_BR
dc.identifier.urlhttps://doi.org/10.1093/eurheartj/ehad662pt_BR
dc.contributor.external(USP) Universidade de São Paulopt_BR
dc.contributor.externalUniversity of Oxfordpt_BR
dc.contributor.external(UDELAR) Universidad de la Repúblicapt_BR
dc.contributor.externaluto de Investigaciones Biológicas Celemente Establept_BR
dc.contributor.externalInstitut Pasteur de Montevideopt_BR
dc.contributor.external(UNICAMP) Universidade Estadual de Campinaspt_BR
dc.contributor.externalStanford Universitypt_BR
dc.contributor.externalForesee Pharmaceuticals, Copt_BR
dc.contributor.external(TSRI) Scripps Research Institutept_BR
dc.subject.keywordoxidative stresspt_BR
dc.subject.keywordaldehydept_BR
dc.subject.keywordmitochondriapt_BR
dc.subject.keywordtherapypt_BR
dc.subject.keywordcardiac diseasespt_BR
dc.relation.ispartofabbreviatedEur Heart Jpt_BR
dc.identifier.citationabntehad662, nov. 2023pt_BR
dc.identifier.citationvancouver2023 Nov; ehad662pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
dc.description.dbindexedYespt_BR
item.openairetypeArticle-
item.grantfulltextnone-
item.fulltextSem Texto completo-
item.languageiso639-1English-
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