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

  • Eur Heart J. 2023 Nov 21;44(44):4696-4712. doi: 10.1093/eurheartj/ehad662.
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
  • 1. Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415 - Butanta, 05508-000 São Paulo-SP, Brazil.
  • 2. Laboratory of Immunology, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
  • 3. Laboratory of Pain and Signaling, Butantan Institute, São Paulo, Brazil.
  • 4. Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, São Paulo, Brazil.
  • 5. Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República (UdelaR), Montevideo, Uruguay.
  • 6. Unidad de Bioquímica y Proteómica Analítica (UByPA), Instituto de Investigaciones Biológicas Celemente Estable & Institut Pasteur de Montevideo, Montevideo, Uruguay.
  • 7. Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), São Paulo, Brazil.
  • 8. Department of Chemical and Systems Biology, Stanford University School of Medicine, CCSR 3145A, 269 Campus Drive, Stanford, CA 94305, USA.
  • 9. Foresee Pharmaceuticals, Co., Ltd, Taipei, Taiwan.
  • 10. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
  • 11. Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Minas Gerais, Brazil.
  • 12. Brazilian National Institute of Vaccine Science and Technology, Federal University of Minas Gerais, Minas Gerais, Brazil.
PMID: 37944136 DOI: 10.1093/eurheartj/ehad662
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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