European Heart Journal

, volume 44 , issue 44 , pages 4696-4712

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}

Hide authors affiliations Show authors affiliations: 12 affiliations

Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo , Av. Prof. Lineu Prestes, 2415 - Butanta, 05508-000 São Paulo-SP , Brazil |

Laboratory of Immunology, Heart Institute, University of São Paulo School of Medicine , São Paulo , Brazil |

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 |

Publication type: Journal Article

Publication date: 2023-11-07

Oxford University Press

European Heart Journal

scimago Q1

wos Q1

SJR: 4.987

CiteScore: 40.3

Impact factor: 35.6

ISSN: 0195668X, 15229645

DOI: 10.1093/eurheartj/ehad662

Copy DOI

PubMed ID: 37944136

Cardiology and Cardiovascular Medicine

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.

Found

Top-30

Journals

	1 2
European Heart Journal	European Heart Journal, 2, 16.67% European Heart Journal 2 publications, 16.67%
Current Opinion in Endocrine and Metabolic Research	Current Opinion in Endocrine and Metabolic Research, 1, 8.33% Current Opinion in Endocrine and Metabolic Research 1 publication, 8.33%
Medicinal Chemistry Research	Medicinal Chemistry Research, 1, 8.33% Medicinal Chemistry Research 1 publication, 8.33%
Journal of Physiology	Journal of Physiology, 1, 8.33% Journal of Physiology 1 publication, 8.33%
Military Medical Research	Military Medical Research, 1, 8.33% Military Medical Research 1 publication, 8.33%
Circulation	Circulation, 1, 8.33% Circulation 1 publication, 8.33%
Advanced Materials	Advanced Materials, 1, 8.33% Advanced Materials 1 publication, 8.33%
Biochemical Pharmacology	Biochemical Pharmacology, 1, 8.33% Biochemical Pharmacology 1 publication, 8.33%
International Journal of Molecular Sciences	International Journal of Molecular Sciences, 1, 8.33% International Journal of Molecular Sciences 1 publication, 8.33%
Mediators of Inflammation	Mediators of Inflammation, 1, 8.33% Mediators of Inflammation 1 publication, 8.33%
	1 2

Publishers

	1 2
Oxford University Press	Oxford University Press, 2, 16.67% Oxford University Press 2 publications, 16.67%
Elsevier	Elsevier, 2, 16.67% Elsevier 2 publications, 16.67%
Springer Nature	Springer Nature, 2, 16.67% Springer Nature 2 publications, 16.67%
Wiley	Wiley, 2, 16.67% Wiley 2 publications, 16.67%
Cold Spring Harbor Laboratory	Cold Spring Harbor Laboratory, 1, 8.33% Cold Spring Harbor Laboratory 1 publication, 8.33%
Ovid Technologies (Wolters Kluwer Health)	Ovid Technologies (Wolters Kluwer Health), 1, 8.33% Ovid Technologies (Wolters Kluwer Health) 1 publication, 8.33%
MDPI	MDPI, 1, 8.33% MDPI 1 publication, 8.33%
Hindawi Limited	Hindawi Limited, 1, 8.33% Hindawi Limited 1 publication, 8.33%
	1 2

We do not take into account publications without a DOI.
Statistics recalculated weekly.

Are you a researcher?

Create a profile to get free access to personal recommendations for colleagues and new articles.

Metrics

Cite this

GOST |

Cite this

GOST Copy

Kiyuna L. A. et al. 4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification // European Heart Journal. 2023. Vol. 44. No. 44. pp. 4696-4712.

GOST all authors (up to 50) Copy

Kiyuna L. A., Candido D. S., Bechara L. R. G., Jesus I. C. G., Ramalho L. S., Krum B., Albuquerque R. P., Campos J. C., Bozi L. H. M., Zambelli V. O., Alves A. N., Campolo N., Mastrogiovanni M., Bartesaghi S., Leyva A., Durán R., Radi R., Arantes G., Cunha‐Neto E., Mori M. A., Chen C., Yang W., Mochly-Rosen D., Macrae I. J., Ferreira L. R. P., Ferreira J. C. 4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification // European Heart Journal. 2023. Vol. 44. No. 44. pp. 4696-4712.

RIS |

Cite this

RIS Copy

TY - JOUR

DO - 10.1093/eurheartj/ehad662

UR - https://doi.org/10.1093/eurheartj/ehad662

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

T2 - European Heart Journal

AU - Kiyuna, Ligia A.

AU - Candido, Darlan S

AU - Bechara, Luiz R. G.

AU - Jesus, Itamar C G

AU - Ramalho, Lisley S

AU - Krum, Barbara

AU - Albuquerque, Ruda P.

AU - Campos, Juliane C

AU - Bozi, Luiz H M

AU - Zambelli, Vanessa O

AU - Alves, Ariane N

AU - Campolo, Nicolás

AU - Mastrogiovanni, Mauricio

AU - Bartesaghi, Silvina

AU - Leyva, Alejandro

AU - Durán, Rosario

AU - Radi, Rafael

AU - Arantes, Guilherme M.

AU - Cunha‐Neto, Edécio

AU - Mori, Marcelo A.

AU - Chen, Che-Hong

AU - Yang, WenJin

AU - Mochly-Rosen, Daria

AU - Macrae, Ian J

AU - Ferreira, Ludmila R. P.

AU - Ferreira, Julio C.B.

PY - 2023

DA - 2023/11/07

PB - Oxford University Press

SP - 4696-4712

IS - 44

VL - 44

PMID - 37944136

SN - 0195-668X

SN - 1522-9645

ER -

BibTex |

Cite this

BibTex (up to 50 authors) Copy

@article{2023_Kiyuna,

author = {Ligia A. Kiyuna and Darlan S Candido and Luiz R. G. Bechara and Itamar C G Jesus and Lisley S Ramalho and Barbara Krum and Ruda P. Albuquerque and Juliane C Campos and Luiz H M Bozi and Vanessa O Zambelli and Ariane N Alves and Nicolás Campolo and Mauricio Mastrogiovanni and Silvina Bartesaghi and Alejandro Leyva and Rosario Durán and Rafael Radi and Guilherme M. Arantes and Edécio Cunha‐Neto and Marcelo A. Mori and Che-Hong Chen and WenJin Yang and Daria Mochly-Rosen and Ian J Macrae and Ludmila R. P. Ferreira and Julio C.B. Ferreira},

title = {4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification},

journal = {European Heart Journal},

year = {2023},

volume = {44},

publisher = {Oxford University Press},

month = {nov},

url = {https://doi.org/10.1093/eurheartj/ehad662},

number = {44},

pages = {4696--4712},

doi = {10.1093/eurheartj/ehad662}

}

MLA

Cite this

MLA Copy

Kiyuna, Ligia A., et al. “4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification.” European Heart Journal, vol. 44, no. 44, Nov. 2023, pp. 4696-4712. https://doi.org/10.1093/eurheartj/ehad662.

Publisher

Oxford University Press

Journal

European Heart Journal

scimago Q1

wos Q1

SJR

4.987

CiteScore

40.3

Impact factor

35.6

ISSN

0195668X (Print)

15229645 (Electronic)

Profiles

Daria Mochly-Rosen