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

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorKIYUNA, Ligia A.
dc.contributor.authorCANDIDO, Darlan S.
dc.contributor.authorBECHARA, Luiz R. G.
dc.contributor.authorJESUS, Itamar C. G.
dc.contributor.authorRAMALHO, Lisley S.
dc.contributor.authorKRUM, Barbara
dc.contributor.authorALBUQUERQUE, Ruda P.
dc.contributor.authorCAMPOS, Juliane C.
dc.contributor.authorBOZI, Luiz H. M.
dc.contributor.authorZAMBELLI, Vanessa O.
dc.contributor.authorALVES, Ariane N.
dc.contributor.authorCAMPOLO, Nicolas
dc.contributor.authorMASTROGIOVANNI, Mauricio
dc.contributor.authorBARTESAGHI, Silvina
dc.contributor.authorLEYVA, Alejandro
dc.contributor.authorDURAN, Rosario
dc.contributor.authorRADI, Rafael
dc.contributor.authorARANTES, Guilherme M.
dc.contributor.authorCUNHA-NETO, Edecio
dc.contributor.authorMORI, Marcelo A.
dc.contributor.authorCHEN, Che-Hong
dc.contributor.authorYANG, Wenjin
dc.contributor.authorMOCHLY-ROSEN, Daria
dc.contributor.authorMACRAE, Ian J.
dc.contributor.authorFERREIRA, Ludmila R. P.
dc.contributor.authorFERREIRA, Julio C. B.
dc.date.accessioned2024-04-05T19:28:44Z
dc.date.available2024-04-05T19:28:44Z
dc.date.issued2023
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. Structured Graphical Abstract The vicious cycle of heart failure (HF). (i) Impaired aldehyde metabolism by aldehyde dehydrogenase 2 (ALDH2); (ii) accumulation of 4-hydroxynonenal (4-HNE), a reactive aldehyde by-product of mitochondrial dysfunction; (iii) direct 4-HNE inhibition of Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis; and (iv) overall impairment of miRNA biogenesis, which negatively impacts HF outcome. Blue and red arrows/inhibitors represent the vicious cycle of HF and the benefits of small molecule activators of ALDH2 in HF, respectively.eng
dc.description.indexMEDLINE
dc.description.indexPubMed
dc.description.indexScopus
dc.description.indexDimensions
dc.description.indexWoS
dc.description.sponsorshipWe thank Dr Peng Jin at Emory for providing the RNAi-293-EGFP/RFP cells. We thank Foresee Pharmaceuticals Co., Ltd for providing AD-9308 and AD-5591 compounds.
dc.identifier.citationEUROPEAN HEART JOURNAL, v.44, n.44, Special Issue, p.4696-4712, 2023
dc.identifier.doi10.1093/eurheartj/ehad662
dc.identifier.eissn1522-9645
dc.identifier.issn0195-668X
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/58757
dc.language.isoeng
dc.publisherOXFORD UNIV PRESSeng
dc.relation.ispartofEuropean Heart Journal
dc.rightsrestrictedAccesseng
dc.rights.holderCopyright OXFORD UNIV PRESSeng
dc.subjectOxidative stresseng
dc.subjectAldehydeeng
dc.subjectMitochondriaeng
dc.subjectTherapyeng
dc.subjectCardiac diseaseseng
dc.subject.otheraldehyde dehydrogenase 2eng
dc.subject.othercardiomyopathyeng
dc.subject.otheractivationeng
dc.subject.othermechanismeng
dc.subject.othercleavageeng
dc.subject.otherdeletioneng
dc.subject.otherstresseng
dc.subject.wosCardiac & Cardiovascular Systemseng
dc.title4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modificationeng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.affiliation.countryTaiwan
hcfmusp.affiliation.countryAlemanha
hcfmusp.affiliation.countryUruguai
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryisode
hcfmusp.affiliation.countryisouy
hcfmusp.affiliation.countryisous
hcfmusp.affiliation.countryisotw
hcfmusp.author.externalKIYUNA, Ligia A.:Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Ave Lineu Prestes 2415, BR-05508900 Sao Paulo, SP, Brazil
hcfmusp.author.externalBECHARA, Luiz R. G.:Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Ave Lineu Prestes 2415, BR-05508900 Sao Paulo, SP, Brazil
hcfmusp.author.externalJESUS, Itamar C. G.:Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Ave Lineu Prestes 2415, BR-05508900 Sao Paulo, SP, Brazil
hcfmusp.author.externalRAMALHO, Lisley S.:Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Ave Lineu Prestes 2415, BR-05508900 Sao Paulo, SP, Brazil
hcfmusp.author.externalKRUM, Barbara:Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Ave Lineu Prestes 2415, BR-05508900 Sao Paulo, SP, Brazil
hcfmusp.author.externalALBUQUERQUE, Ruda P.:Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Ave Lineu Prestes 2415, BR-05508900 Sao Paulo, SP, Brazil
hcfmusp.author.externalCAMPOS, Juliane C.:Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Ave Lineu Prestes 2415, BR-05508900 Sao Paulo, SP, Brazil
hcfmusp.author.externalBOZI, Luiz H. M.:Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Ave Lineu Prestes 2415, BR-05508900 Sao Paulo, SP, Brazil
hcfmusp.author.externalZAMBELLI, Vanessa O.:Butantan Inst, Lab Pain & Signaling, Sao Paulo, Brazil
hcfmusp.author.externalALVES, Ariane N.:Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo, Brazil; Tech Univ Berlin, Inst Chem, Berlin, Germany
hcfmusp.author.externalCAMPOLO, Nicolas:Univ Republ UdelaR, Fac Med, Dept Bioquim, Montevideo, Uruguay; Univ Republ UdelaR, Fac Med, Ctr Invest Biomed CEINBIO, Montevideo, Uruguay
hcfmusp.author.externalMASTROGIOVANNI, Mauricio:Univ Republ UdelaR, Fac Med, Dept Bioquim, Montevideo, Uruguay; Univ Republ UdelaR, Fac Med, Ctr Invest Biomed CEINBIO, Montevideo, Uruguay
hcfmusp.author.externalBARTESAGHI, Silvina:Univ Republ UdelaR, Fac Med, Dept Bioquim, Montevideo, Uruguay; Univ Republ UdelaR, Fac Med, Ctr Invest Biomed CEINBIO, Montevideo, Uruguay
hcfmusp.author.externalLEYVA, Alejandro:Inst Invest Biol Celemente Estable, Unidad Bioquim & Prote Analit UByPA, Montevideo, Uruguay; Inst Pasteur Montevideo, Montevideo, Uruguay
hcfmusp.author.externalDURAN, Rosario:Inst Invest Biol Celemente Estable, Unidad Bioquim & Prote Analit UByPA, Montevideo, Uruguay; Inst Pasteur Montevideo, Montevideo, Uruguay
hcfmusp.author.externalRADI, Rafael:Univ Republ UdelaR, Fac Med, Dept Bioquim, Montevideo, Uruguay; Univ Republ UdelaR, Fac Med, Ctr Invest Biomed CEINBIO, Montevideo, Uruguay
hcfmusp.author.externalARANTES, Guilherme M.:Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo, Brazil
hcfmusp.author.externalMORI, Marcelo A.:Univ Campinas Unicamp, Inst Biol, Dept Biochem & Tissue Biol, Sao Paulo, Brazil
hcfmusp.author.externalCHEN, Che-Hong:Stanford Univ, Sch Med, Dept Chem & Syst Biol, CCSR 3145A,269 Campus Dr, Stanford, CA 94305 USA
hcfmusp.author.externalYANG, Wenjin:Foresee Pharmaceut Co Ltd, Taipei, Taiwan
hcfmusp.author.externalMOCHLY-ROSEN, Daria:Stanford Univ, Sch Med, Dept Chem & Syst Biol, CCSR 3145A,269 Campus Dr, Stanford, CA 94305 USA
hcfmusp.author.externalMACRAE, Ian J.:Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA USA
hcfmusp.author.externalFERREIRA, Ludmila R. P.:Univ Sao Paulo, Heart Inst, Sch Med, Lab Immunol, Sao Paulo, Brazil; Univ Fed Minas Gerais, Inst Biol Sci, Dept Morphol, Belo Horizonte, MG, Brazil; Univ Fed Minas Gerais, Brazilian Natl Inst Vaccine Sci & Technol, Belo Horizonte, MG, Brazil
hcfmusp.author.externalFERREIRA, Julio C. B.:Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Ave Lineu Prestes 2415, BR-05508900 Sao Paulo, SP, Brazil; Stanford Univ, Sch Med, Dept Chem & Syst Biol, CCSR 3145A,269 Campus Dr, Stanford, CA 94305 USA
hcfmusp.citation.scopus2
hcfmusp.contributor.author-fmusphcDARLAN DA SILVA CANDIDO
hcfmusp.contributor.author-fmusphcEDECIO CUNHA NETO
hcfmusp.description.beginpage4696
hcfmusp.description.endpage4712
hcfmusp.description.issue44
hcfmusp.description.issueSpecial Issue
hcfmusp.description.volume44
hcfmusp.origemWOS
hcfmusp.origem.dimensionspub.1165808394
hcfmusp.origem.pubmed37944136
hcfmusp.origem.scopus2-s2.0-85178536462
hcfmusp.origem.wosWOS:001098101200001
hcfmusp.publisher.cityOXFORDeng
hcfmusp.publisher.countryENGLANDeng
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