4-羟基壬烯醛通过 Dicer 翻译后修饰损害心力衰竭中的 miRNA 成熟。

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

机构信息

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.

出版信息

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

DOI:10.1093/eurheartj/ehad662

PMID:37944136

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.

摘要

背景与目的

开发新型疗法以应对心力衰竭这一全球公共卫生负担仍然具有挑战性。本研究旨在探讨 4-羟壬烯醛（4-HNE）在心力衰竭中的有害作用的潜在机制和治疗方法。

方法

应用生化、功能和组织化学测量方法鉴定大鼠和人心力衰竭心脏中的 4-HNE 加合物。进行体外研究以验证 4-HNE 靶点。

结果

4-HNE 是心力衰竭中线粒体功能障碍的一种反应性醛类副产物，可使 Dicer 发生共价抑制，Dicer 是 miRNA 生成所必需的 RNase III 内切酶。4-HNE 抑制 Dicer 会损害 miRNA 加工。在机制上，4-HNE 通过分子间相互作用与重组人 Dicer 结合，以浓度和时间依赖的方式破坏 Dicer 的活性和稳定性。用二硫苏糖醇中和 4-HNE 或替换 Dicer 中的 4-HNE 靶向残基可防止 4-HNE 在体外抑制 Dicer。有趣的是，三种不同心力衰竭病因的终末期人心力衰竭心脏显示出 4-HNE 清除缺陷、Dicer 活性降低和 miRNA 生物发生受损。值得注意的是，通过使用 Alda-1 或其改良的口服生物可利用衍生物 AD-9308 重新激活线粒体醛脱氢酶 2（ALDH2）来促进 4-HNE 清除，可恢复 Dicer 活性。ALDH2 是负责 4-HNE 清除的主要酶。重要的是，这种反应伴随着 miRNA 成熟和心力衰竭的心脏功能/重塑的改善。