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.
Several studies have shown the role of microRNAs (miRNAs) in myocardial dysfunction in response to ischemia/reperfusion (I/R). In this study, we investigated the impact of high fat (HF) diet in the ...myocardial susceptibility to I/R injury, as well as in the expression of miRNA‐29b. Isolated heart experiments using the ex vivo Langendorff perfusion model were used to induce cardiac I/R injury. HF diet‐induced cardiac hypertrophy and impaired cardiac functional recovery after I/R. miRNA‐29b, which targets Col1, was reduced in the heart of HF diet‐fed mice, whereas the cardiac expression of Col1 was increased. In addition, hypoxia–reoxygenation (H/R) reduced the expression of miRNA‐29b in cardiomyoblasts cultures. However, the overexpression of miRNA‐29b in cardiomyoblasts reduced p53 mRNA levels and H/R injury, suggesting that downregulation of miRNA‐29b may be involved in I/R injury. Together, our findings suggest that the reduced expression of miRNA‐29b may be involved in the deteriorated cardiac functional recovery following I/R in obese mice.
Obese mice displayed deteriorated cardiac functional recovery following the ischemia/reperfusion (I/R) injury, which was accompanied by the reduced expression of microRNA (miRNA)‐29b. Hypoxia–reoxygenation (H/R) reduced the expression of miRNA‐29b in cardiomyoblasts cultures. The overexpression of miRNA‐29b attenuated the increased cell death in response to H/R, suggesting that the reduced expression of miRNA‐29b may be involved in the deteriorated cardiac functional recovery following the I/R in obese mice.
