Zaccagnini, G. | bioRxiv Science

bioRxiv2024

miR-210 is essential to retinal homeostasis in fruit flies and mice

miR-210 is one of the most evolutionarily conserved microRNAs. Recent studies in Drosophila melanogaster have unveiled that the absence of miR-210 leads to a progressive retinal degeneration characterized by the accumulation of lipid droplets and disruptions in lipid metabolism. Further investigation into lipid anabolism and catabolism revealed significant alterations in gene expression within these pathways. We provide the first morphological characterization of miR-210 KO mice retinas, highlighting a significant photoreceptor degeneration. While exploring potential parallels between miR-210 KO models in flies and mice, we examined mice lipid metabolism, circadian behaviour, and retinal transcriptome yet found no resemblances, suggesting divergent mechanisms of retinal degeneration between the two species. Simultaneously, analysis of the transcriptome in the brains of miR-210 KO flies revealed the potential existence of a shared upstream mechanism contributing to retinal degeneration in both fruit flies and mammals.

genetics↗

bioRxiv2023

Interleukin 11-induced microRNAs as functional mediators and circulating biomarkers of cardiac fibrosis

BackgroundCardiac fibrosis can be triggered by several pathologies, including ischemic heart disease and aortic stenosis (AS). Cardiac fibrosis is brought about by uncontrolled extracellular matrix (ECM) deposition by myofibroblasts. Interleukin-11 (IL-11) has been firmly demonstrated to be a major trigger of multi-organ fibrosis. However, the molecular mechanisms underpinning IL-11-induced fibrosis requires further characterisation. Recent studies indicate that microRNA (miRNA) dysregulation contributes to the pathogenesis of cardiac fibrosis and can be targeted therapeutically. In this study, we explored the hypothesis that miRNAs act as downstream effectors of IL-11-induced cardiac fibrosis. Moreover, we investigated the translational potential of IL-11-regulated miRNAs as circulating biomarkers of cardiac fibrosis in AS patients. Methods and ResultsUsing computational approaches, we identified miRNA-497-5p and miRNA-27b-5p as potential new downstream profibrotic effectors of IL-11 in fibroblasts. We next confirmed that both miRNAs increased in healthy rat CF stimulated with IL-11 and in CF derived from post-infarction failing hearts. At the functional level, miRNA-497-5p and miRNA-27b-5p inhibition indirectly reduced the mRNA expression of collagen 1 (Col1a1). Conversely, transfection of CFs with mimics for each of the two miRNAs promoted fibroblast-to-myofibroblast transition and increased Col1a1 levels. We provided evidences that miRNA-27b-5p and miRNA-497-5p converge to promote hypoxia-inducible factor 1 signalling, by targeting its regulator EGLN (PHD) family members. The clinical relevance of our findings was confirmed using left ventricle (LV) specimens obtained from surgical patients with AS. The miRNA-27b-5p and miRNA-497-5p measured in the LV, peripheral plasma and plasma extracellular vesicles correlated with the severity of LV fibrosis, indicating these miRNAs potential as new circulating biomarkers of cardiac fibrosis. ConclusionsIn this study, we have newly identified the potential value of miRNA-27b-5p and miRNA-497-5p as actionable biomarkers of the profibrotic response to IL-11 in the heart. Future studies should validate the translational potential of the miRNAs as new clinical biomarkers and therapeutic targets.

molecular biology↗