24 - 4-HNE-mediated post-translational modulation of DICER in heart failure

Abstract

4-hydroxy-2-nonenal (4-HNE) is a major by-product of lipid peroxidation, a process that is exacerbated under oxidative stress conditions. This aldehyde is a very reactive molecule associated with the establishment and progression of many diseases, including cardiovascular diseases. Using mass spectrometry analysis, our group has recently found that 4-HNE directly targets DICER— a critical enzyme for microRNA (miRNA) biology— in failing hearts. Considering that targeted deletion of DICER in the heart leads to dilated cardiomyopathy and heart failure (HF), we hypothesized that 4-HNE adducted DICER could compromise its function and drive cardiac dysfunction. In a post-myocardial infarction-induced HF animal model, we found that DICER activity dropped 46.5% (53,5% ±3,9; n=6) in failing hearts when compared to sham group, followed by a reduction in miRNA levels. Pharmacological activation of aldehyde dehydrogenase 2 (ALDH2), a key mitochondrial enzyme responsible for 4-HNE removal, prevented cardiac 4-HNE protein adduct accumulation and minimized DICER loss of activity (72,15% ±14,6; n=6) in heart failure. Consistent with our in vivo data, H9C2 myoblasts acutely exposed to 50µM 4-HNE showed an increase in 4-HNE-protein adducts followed by a 16,7% reduction (83,3% ±1,2; n=4) in DICER activity. Notably, in vitro experiments using recombinant protein revealed that 4-HNE directly interacts with DICER, and the formation of 4-HNE-DICER adduct causes loss of DICER enzymatic activity in a time- and concentration-dependent manner. Taken together, our findings using animal and cellular models suggest that DICER is impaired under acute and chronic (cardiac dysfunction) aldehyde load. Moreover, a better clearance of cardiac 4-HNE improves both DICER activity and heart failure outcome in rodents. Overall, a better understanding of post-translational DICER regulation and its impact on microRNA profiles will certainly contribute to the discovery/development of improved and novel therapeutic strategies to tackle heart failure.