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. 2023 Nov 21;44(44):4696-4712.
doi: 10.1093/eurheartj/ehad662.

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

Ligia A Kiyuna  1 , Darlan S Candido  2 , Luiz R G Bechara  1 , Itamar C G Jesus  1 , Lisley S Ramalho  1 , Barbara Krum  1 , Ruda P Albuquerque  1 , Juliane C Campos  1 , Luiz H M Bozi  1 , Vanessa O Zambelli  3 , Ariane N Alves  4 , Nicolás Campolo  5 , Mauricio Mastrogiovanni  5 , Silvina Bartesaghi  5 , Alejandro Leyva  6 , Rosario Durán  6 , Rafael Radi  5 , Guilherme M Arantes  4 , Edécio Cunha-Neto  2 , Marcelo A Mori  7 , Che-Hong Chen  8 , Wenjin Yang  9 , Daria Mochly-Rosen  8 , Ian J MacRae  10 , Ludmila R P Ferreira  2   11   12 , Julio C B Ferreira  1   8
Affiliations

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

Ligia A Kiyuna et al. Eur Heart J. .

Abstract

Background 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.

Keywords: Aldehyde; Cardiac diseases; Mitochondria; Oxidative stress; Therapy.

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