Agradecimentos: We 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. This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 2013/07937-8, 2015/22814-5, 2017/16694-2, and 2019/25049-9; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) 303281/2015-4 and 407306/2013-7; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brasil (CAPES) Finance Code 001 and Instituto Nacional de Ciência e Tecnologia and Centro de Pesquisa e Desenvolvimento de Processos Redox em Biomedicina to J.C.B.F. FAPESP 2014/17008-7 and 2019/21856-7 to A.N.A. and G.M.A. Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) APQ-03551-18 and CNPq to L.R.P.F. C.H.C. is supported by National Institutes of Health (NIH) AAA11147 to D.M.R. Comisión Sectorial de Investigación Científica and Espacio Interdisciplinario to R.R. Ver menos

Abstract: 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. 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. 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 Ver menos