Therapeutic modulation of RNA-binding protein Rbm38 facilitates re-endothelialization after arterial injury.

Aims Delayed re-endothelialization after balloon angioplasty in patients with coronary or peripheral artery disease impairs vascular healing and leads to neointimal proliferation. In the present study, we examined the effect of RNA-binding motif protein 38 (Rbm38) during re-endothelialization in a murine model of experimental vascular injury. Methods and results Left common carotid arteries of C57BL/6 mice were electrically denudated and endothelial regeneration was evaluated. Profiling of RNA-binding proteins revealed dysregulated expression of Rbm38 in the denudated and regenerated areas. We next tested the importance of Rbm38 in human umbilical vein endothelial cells (HUVECS) and analysed its effects on cellular proliferation, migration and apoptosis. Rbm38 silencing in vitro demonstrated important beneficial functional effects on migratory capacity and proliferation of endothelial cells. In vivo, local silencing of Rbm38 also improved re-endothelialization of denuded carotid arteries. Luciferase reporter assay identified miR-98 and let-7f to regulate Rbm38 and the positive proliferative properties of Rbm38 silencing in vitro and in vivo were mimicked by therapeutic overexpression of these miRNAs. Conclusion The present data identified Rbm38 as an important factor of the regulation of various endothelial cell functions. Local inhibition of Rbm38 as well as overexpression of the upstream regulators miR-98 and let-7f improved endothelial regeneration in vivo and thus may be a novel therapeutic entry point to avoid endothelial damage after balloon angioplasty

Inhibition of miRNA-212/132 improves the reprogramming of fibroblasts into induced pluripotent stem cells by de-repressing important epigenetic remodelling factors

MicroRNAs (miRNAs) repeatedly have been demonstrated to play important roles in the generation of induced pluripotent stem cells (iPSCs). To further elucidate the molecular mechanisms underlying transcription factor-mediated reprogramming we have established a model, which allows for the efficient screening of whole libraries of miRNAs modulating the generation of iPSCs from murine embryonic fibroblasts. Applying this model, we identified 14 miRNAs effectively inhibiting iPSC generation, including miR-132 and miR-212. Intriguingly, repression of these miRNAs during iPSC generation also resulted in significantly increased reprogramming efficacy. MiRNA target evaluation by qRT-PCR, Western blot, and luciferase assays revealed two crucial epigenetic regulators, the histone acetyl transferase p300 as well as the H3K4 demethylase Jarid1a (KDM5a) to be directly targeted by both miRNAs. Moreover, we demonstrated that siRNA-mediated knockdown of either p300 or Jarid1a recapitulated the miRNA effects and led to a significant decrease in reprogramming efficiency. Thus, conducting a full library miRNA screen we here describe a miRNA family, which markedly reduces generation of iPSC and upon inhibition in turn enhances reprogramming. These miRNAs, at least in part, exert their functions through repression of the epigenetic modulators p300 and Jarid1a, highlighting these two molecules as an endogenous epigenetic roadblock during iPSC generation

Blood-based microRNA profiling in patients with cardiac amyloidosis.

INTRODUCTION:Amyloidosis is caused by dysregulation of protein folding resulting in systemic or organ specific amyloid aggregation. When affecting the heart, amyloidosis can cause severe heart failure, which is associated with a high morbidity and mortality. Different subtypes of cardiac amyloidosis exist e.g. transthyretin cardiac amyloidosis and senile cardiac amyloidosis. Today, diagnostics is primarily based on cardiac biopsies and no clinically used circulating blood-based biomarkers existing. Therefore, our aim was to identify circulating microRNAs in patients with different forms of amyloidosis. METHODS:Blood was collected from healthy subjects (n = 10), patients with reduced ejection fraction (EF < 35%; n = 10), patients affected by transthyretin cardiac amyloidosis (n = 13) as well as senile cardiac amyloidosis (n = 11). After performing TaqMan array profiling, promising candidates, in particular miR-99a-5p, miR-122-5p, miR-27a-3p, miR-221-3p, miR-1180-3p, miR-155-5p, miR-339-3p, miR-574-3p, miR-342-3p and miR-329-3p were validated via quantitative real time PCR. RESULTS:The validation experiments revealed a significant upregulation of miR-339-3p in patients affected with senile cardiac amyloidosis compared to controls. This corresponded to the array profiling results. In contrast, there was no deregulation in the other patient groups. CONCLUSION:MiR-339-3p was increased in blood of patients with senile cardiac amyloidosis. Therefore, miR-339-3p is a potential candidate as biomarker for senile cardiac amyloidosis in future studies. Larger patient cohorts should be investigated

Sorodiscordância na atenção às pessoas com HIV/AIDS: implicações para o enfermeiro Serodiscordance in care for people with HIV/AIDS: implications for nurses

Objetivo: analisar a produção científica sobre a prática sexual em casais sorodiscordantes e destacar as implicações para a prática do enfermeiro. Método: trata-se de uma revisão integrativa realizada nas bases de dados da Biblioteca Virtual em Saúde, Lilacs, SciELO, PubMED, CINAHL, sendo selecionados 12 artigos que atenderam aos critérios de inclusão, publicados de 2009 a 2014. Resultados: a maioria dos artigos foram publicados por enfermeiros em 2011 e 2013 nas revistas Caderno de Saúde Pública, Temas em Psicologia e Revista da Escola de Enfermagem USP; sendo prevalente o descritor, casamento. As publicações foram agrupadas em duas categorias temáticas: Práticas sexuais após o diagnóstico do HIV; e Sorodiscordância na vida afetivo-sexual de portadores do HIV/AIDS: implicações para o enfermeiro. Conclusões: ações de enfermagem pautadas na orientação sexual contribuam para melhorar a qualidade de vida dos sorodiscordantes

Serum circular RNAs act as blood-based biomarkers for hypertrophic obstructive cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and is associated with a high risk of sudden cardiac death. HCM is characterized by pronounced hypertrophy of cardiomyocytes, fiber disarray and development of fibrosis and can be divided into a non-obstructive (HNCM) and obstructive form (HOCM) therefore requiring personalized therapeutic therapies. In the present study, we investigated the expression patterns of several circulating circular RNAs (circRNAs) as potential biomarkers in patients with HCM. We included 64 patients with HCM and 53 healthy controls to the study and quantitatively measured the expression of a set of circRNAs already known to be associated with cardiac diseases (circDNAJC6) and/or being highly abundant in blood (circTMEM56 and circMBOAT2). Abundancy of circRNAs was then correlated to relevant clinical parameters. Serum expression levels of circRNAs DNAJC6, TMEM56 and MBOAT2 were downregulated in patients with HCM. The inverse association between circRNA levels and HCM remained unchanged even after adjusting for confounding factors. All circRNAs, evaluated separately or in combination, showed a robust discrimination capacity when comparing control subjects with HCM, HNCM or HOCM patients (AUC from 0.722 to 0.949). Two circRNAs, circTMEM56 and circDNAJC6, significantly negatively correlated with echocardiographic parameters for HOCM. Collectively, circulating circRNAs DNAJC6, TMEM56 and MBOAT2 can distinguish between healthy and HCM patients. In addition, circTMEM56 and circDNAJC6 could serve as indicators of disease severity in patients with HOCM. Thus, circRNAs emerge as novel biomarkers for HCM facilitating the clinical decision making in a personalized manner.This work was supported by Junge Akademie, MHH (to K.S.), ERC grant Longheart (to T.T.) and Deutsche Forschungsgemeinschaft, TRR_267 (to T.T.) and KFO311 (to T.T. and J.B. (D.d.G.C. was a recipient of a Juan de la Cierva-Incorporación grant from the Ministry of Science Innovation and Universities (IJCI-2016-29393). CIBER Cardiovascular (CB16/11/00403 to DdG-C) is a project from Carlos III Health Institute

MicroRNAs regulating superoxide dismutase 2 are new circulating biomarkers of heart failure

International audienc

Development of Long Noncoding RNA-Based Strategies to Modulate Tissue Vascularization.

Long noncoding ribonucleic acids (lncRNAs) are a subclass of regulatory noncoding ribonucleic acids for which expression and function in human endothelial cells and angiogenic processes is not well studied

miR-625-3p expression is regulated during CD8+ T cell reconstitution in vivo.

<p>(A) Viable CD8+ T cells were quantified (grey triangles) and isolated by FACS sorting from peripheral blood samples collected on days 25 (n = 22), 45 (n = 53), 90 (n = 45) and 150 (n = 17) after allogeneic SCT. Subsequently, the relative miR-625-3p expression (black circles) was determined. Left Y-axis: Mean relative miR-625-3p expression calculated by miR-625-3p [RQ]/mean RNU48/U6 snRNA [RQ]. RQ: relative quantity. Right Y-axis: Mean CD8+ T cell count /μl at the time of blood collection (±5 days). Error bars indicate standard error of mean. All measurements were performed in duplicates. Statistical comparisons was calculated in comparison with the miR-625-3p expression in CD8+ T cells of healthy donors by Mann-Whitney U test; *indicates p<0.05. (B) Correlation analysis between relative miR-625-3p expression in patient derived CD8+ T cells (black circles) and the exact time of collection after allogeneic SCT is shown. The relationship between collection time and miR-625-3p expression in CD8+ T cells was analyzed by Spearman correlation coefficient (R²) analysis.</p