Littérature scientifique sur le sujet « MiR129-5p »

Outcome prognostication after cardiac arrest (CA) is challenging. Current multimodal prediction approaches would benefit from new biomarkers. MicroRNAs constitute a novel class of disease markers and circulating levels of brain-enriched ones have been associated with outcome after CA. To determine whether these levels reflect the extent of brain damage in CA patients, we assessed their correlation with neuron-specific enolase (NSE), a marker of brain damage. Blood samples taken 48 h after return of spontaneous circulation from two groups of patients from the Targeted Temperature Management trial were used. Patients were grouped depending on their neurological outcome at six months. Circulating levels of microRNAs were assessed by sequencing. NSE was measured at the same time-point. Among the 673 microRNAs detected, brain-enriched miR9-3p, miR124-3p and miR129-5p positively correlated with NSE levels (all p < 0.001). Interestingly, these correlations were absent when only the good outcome group was analyzed (p > 0.5). Moreover, these correlations were unaffected by demographic and clinical characteristics. All three microRNAs predicted neurological outcome at 6 months. Circulating levels of brain-enriched microRNAs are correlated with NSE levels and hence can reflect the extent of brain injury in patients after CA. This observation strengthens the potential of brain-enriched microRNAs to aid in outcome prognostication after CA.

We have previously shown that short term treatment of estrogen(E2) can rescue advance heart failure(HF) and decreases associated fibrosis. We hypothesized that E2 can reduce fibrosis by regulating the levels of specific microRNAs including miR129-5p(miR129) through ERβ mediated mechanism. We used transaortic constriction to induce HF in male mice, and once the ejection fraction (EF) reached ~30%, one group of animals was sacrificed (HF), and the other group received 17b-estradiol via a subcutaneous pellet implant (0.012mg/pellet, n=16) (E2) for 10 days. Sham-operated mice served as CTRL. Serial echocardiography was performed to monitor cardiac structure and function. Short-term E2 treatment rescued pressure overload-induced decompensated HF in mice by restoring the EF from 33.17±1.12% to 53.05±1.29 (p <0.001, n=16). E2 decreased both interstitial and perivascular fibrosis in HF. Microarray analysis comparing HF with E2 revealed ~70 microRNAs including miR129 regulated by E2. qPCR validation revealed that E2 treatment upregulates miR129 by 2 folds compared to HF restoring it to CTRL levels. Treatment of HF with ERβ agonist (DPN), but not ERα agonist (PPT) resulted in the upregulation of miR129 indicating the E2 mediated induction of miR129 is mediated through ERβ. In vitro, angiotensin II treatment significantly downregulated miR129 expression in neonatal rat fibroblasts (NRVF) which was restored by E2 and DPN but not by E2+ERβ antagonist (PHPT) further confirming the role of ERβ in regulating miR129. In vitro, OE of miR129 in both neonatal and adult rat cardiac fibroblasts (ARVF) resulted in significant downregulation of transcripts of many in-silico predicted pro-fibrotic target genes including EGFR, RUNX, GREM1, COL2A, PDGFA, PDGFRA and the transcription factor SOX4. OE of miR129 in fibroblasts also resulted in downregulation of EGFR protein. Gain of miR129 prevented the transition of fibroblasts to myofibroblasts in both NRVF and ARVF and inhibited fibroblast proliferation in vitro. In conclusion, E2 treatment during HF induces miR129 likely through ERβ. MiR129 represses fibrosis by targeting key genes associated with cardiac fibrosis, inhibits fibroblast proliferation and fibroblast to myofibroblast transition.

Amyotrophic Lateral Sclerosis (ALS) is a progressive fatal neuromuscular disease characterized by selective motorneurons loss. Since mutations in TARDBP and FUS genes were discovered to cause familial form of ALS and TDP-43 and FUS proteins play important roles in RNA metabolism, transcriptional alterations emerged as potential pathogenic mechanism. RNA metabolism include several aspects of RNA regulation such as RNA transcription, maturations and regulation. In this study we have investigated two different fields of RNA metabolism: the first one concerns to microRNAs (miRNA) which regulate translation of several mRNAs, and the second one is related to a specific muscular and neuronal transcription factor potential involved in ALS. First, we have assessed any selected miRNAs with neuronal functions in human neuroblastoma cell lines expressing the pathological SOD1(G93A) mutation and we found a small group of altered miRNAs. Subsequently, we explored these miRNAs in the spinal cord of transgenic SOD1(G93A) mice identified a panel of targets commonly altered in SOD1 ALS models. Furthermore, we assessed the expression levels of a panel of selected miRNAs in circulating cells obtain from patients affected by sporadic ALS form (sALS). This approach let us to identify two microRNAs (miR129-5p and miR200c) that were up-regulated in both SOD1 ALS models and in blood cells of patients with sporadic form of disease, evidencing two possible parameters potentially involved in the pathogenesis of both the sporadic and the familial form of ALS. Moreover, we also identified HuD protein as a potential molecular target of miR129-5p; this protein has been previously reported to play a role in neuronal plasticity and in recovery from axonal injury. Indeed, in a cell line stably overespressing mir129-5p we found a reduction in neurite outgrowth and decreased expression levels of differentiation markers with respect to control cells. Taken together these data strongly suggest that microRNAs play a role in ALS pathogenesis and in particular that mir129-5p can affect neuronal plasticity by modulating HuD levels. In the second part of the study we investigated the possible involvement of two members of myocyte enhancer factor 2 (MEF2) family in the pathogenesis of ALS. MEF2D and MEF2C are transcriptional factors playing crucial roles both in muscle and in neuron development and maintenance. We have performed gene expression analysis in peripheral blood mononuclear cells (PBMCs), we showed a strong increased in MEF2D and MEF2C levels both in sporadic and in familial ALS (SOD1+) patients and a direct correlation between MEF2D and MEF2C mRNA levels was observed in patients and controls. Although protein levels were unchanged, a different pattern of distribution for MEF2D-MEF2C proteins in patient cells was found, suggesting a possible lack of their function. To evaluate the transcriptional activity of MEF2 proteins mRNA levels of their downstream targets BDNF, KLF6, RUFY3 and NPEPPS were assessed. Our results showed a significant down-regulation of BDNF, KLF6 and RUFY3 levels confirming that transcriptional activity of both MEF2D and MEF2C isoforms was altered in sporadic and familial ALS patients. In conclusion, our results evidenced a systemic alteration of MEF2D and MEF2C pathways in ALS patients independently from the presence of SOD1 gene mutations, highlighting a possible common feature between the sporadic and the familiar form of disease which are characterized by a different clinical phenotype and pathological hallmarks.