Key result
ALDH2 activation improves cardiac function in preclinical heart failure by decreasing 4-HNE and restoring Dicer.
Why the study?
Developing novel therapies for heart failure remains challenging, motivating investigation into the underlying mechanisms and potential treatment for the deleterious effects of 4-hydroxynonenal.
Does pharmacological ALDH2 activation using Alda-1 or AD-9308 improve Dicer activity, miRNA biogenesis, and cardiac function in preclinical models of heart failure?
Does pharmacological ALDH2 activation using Alda-1 or AD-9308 improve Dicer activity, miRNA biogenesis, and cardiac function in preclinical models of heart failure?
Pharmacological activation of ALDH2 reduces 4-HNE levels, restoring Dicer activity and miRNA biogenesis, which improves cardiac function in preclinical heart failure models.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Every cell has hundreds or sometimes thousands of mitochondria, which produce enough aldehyde to poison the entire cell when they aren't running properly. We discovered in this latest study that too much of 4-hydroxynonenal switches off a vital event for the cell: processing of microRNAs.”
“We have established a long-standing and very stimulating collaboration with Foresee, and over the past few years have generated a very compelling body of translational data related to ALDH2 biology and the therapeutic applications of Foresee's ALDH2 activators in cardiovascular and muscle diseases. This new publication elucidates a novel mechanism of disease pathology in heart failure and allows us to better understand the pathways by which their ALDH2 activators significantly improve cardiac function and reduced remodeling in the rodent heart failure models.”
“The data further builds our understanding of the biological role of ALDH2 in cardiometabolic diseases and further strengthens our view on the promise of our ALDH2 activators across a diverse group of diseases where mitochondrial dysfunction plays a pivotal role.”
No immediate clinical implications; leaves open 4-HNE-Dicer targeting as a heart failure therapy.
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.
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Kiyuna et al. (2023) studied Heart failure. Pharmacological ALDH2 activation (Alda-1 or AD-9308) was evaluated on Dicer activity, miRNA biogenesis, and cardiac function/remodelling. Pharmacological ALDH2 activation decreased cardiac 4-HNE levels, restoring Dicer activity, miRNA maturation, and cardiac function in a pre-clinical model of heart failure.
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