Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSPKIYUNA, Ligia A.CANDIDO, Darlan S.BECHARA, Luiz R. G.JESUS, Itamar C. G.RAMALHO, Lisley S.KRUM, BarbaraALBUQUERQUE, Ruda P.CAMPOS, Juliane C.BOZI, Luiz H. M.ZAMBELLI, Vanessa O.ALVES, Ariane N.CAMPOLO, NicolasMASTROGIOVANNI, MauricioBARTESAGHI, SilvinaLEYVA, AlejandroDURAN, RosarioRADI, RafaelARANTES, Guilherme M.CUNHA-NETO, EdecioMORI, Marcelo A.CHEN, Che-HongYANG, WenjinMOCHLY-ROSEN, DariaMACRAE, Ian J.FERREIRA, Ludmila R. P.FERREIRA, Julio C. B.2024-04-052024-04-052023EUROPEAN HEART JOURNAL, v.44, n.44, Special Issue, p.4696-4712, 20230195-668Xhttps://observatorio.fm.usp.br/handle/OPI/58757Background 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.engrestrictedAccessOxidative stressAldehydeMitochondriaTherapyCardiac diseasesaldehyde dehydrogenase 2cardiomyopathyactivationmechanismcleavagedeletionstressarticleCopyright OXFORD UNIV PRESS10.1093/eurheartj/ehad662Cardiac & Cardiovascular Systems1522-9645