Heart failure & cardiomyopathies
4-Hydroxynonenal impairs microRNA (miRNA) maturation in heart failure via Dicer post-translational modification
Authors' conclusion
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
Study context
- Population
- Rat and human failing hearts; in vitro studies
Main finding
As reported in the abstract
- 4-HNE covalently inhibits Dicer, impairing miRNA processing
- 4-HNE binds recombinant human Dicer, disrupting its activity and stability in a concentration- and time-dependent manner
- Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted Dicer residues prevents Dicer inhibition in vitro
- End-stage human failing hearts (3 HF aetiologies): defective 4-HNE clearance, decreased Dicer activity, impaired miRNA biogenesis
- ALDH2 re-activation with Alda-1 or AD-9308 restores Dicer activity, with improved miRNA maturation and cardiac function/remodelling in a pre-clinical HF model
Original publication
4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification. Eur Heart J. Published 7 November 2023. doi:10.
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