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Seronde M.-F.,University Hospital | Seronde M.-F.,University Paris Diderot | Vausort M.,Laboratory of Cardiovascular Research | Gayat E.,University Paris Diderot | And 13 more authors.
PLoS ONE | Year: 2015

Background: The biomarker value of circulating microRNAs (miRNAs) has been extensively addressed in patients with acute coronary syndrome. However, prognostic performances of miRNAs in patients with acute heart failure (AHF) has received less attention. Methods: A test cohort of 294 patients with acute dyspnea (236 AHF and 58 non-AHF) and 44 patients with stable chronic heart failure (CHF), and an independent validation cohort of 711 AHF patients, were used. Admission levels of miR-1/-21/-23/-126/-423-5p were assessed in plasma samples. Results: In the test cohort, admission levels of miR-1 were lower in AHF and stable CHF patients compared to non-AHF patients (p = 0.0016). Levels of miR-126 and miR-423-5p were lower in AHF and in non-AHF patients compared to stable CHF patients (both p<0.001). Interestingly, admission levels of miR-423-5p were lower in patients who were re-admitted to the hospital in the year following the index hospitalization compared to patients who were not (p = 0.0001). Adjusted odds ratio [95% confidence interval] for one-year readmission was 0.70 [0.53-0.93] for miR-423-5p (p = 0.01). In the validation cohort, admission levels of miR-423- 5p predicted 1-year mortality with an adjusted odds ratio [95% confidence interval] of 0.54 [0.36-0.82], p = 0.004. Patients within the lowest quartile of miR-423-5p were at high risk of long-term mortality (p = 0.02). Conclusions: In AHF patients, low circulating levels of miR-423-5p at presentation are associated with a poor long-term outcome. This study supports the value of miR-423-5p as a prognostic biomarker of AHF. © 2015 Seronde et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Thum T.,Institute of Molecular and Translational Therapeutic Strategies IMTTS | Thum T.,Imperial College London | Condorelli G.,Humanitas Clinical and Research Center | Condorelli G.,Institute of Genetics and Biomedical Research | And 2 more authors.
Circulation Research | Year: 2015

RNAs not encoding proteins have gained prominence over the last couple of decades as fundamental regulators of cellular function. Not surprisingly, their dysregulation is increasingly being linked to pathology. Here, we review recent reports investigating the pathophysiological relevance of this species of RNA for the cardiovascular system, concentrating mainly on recent findings on long noncoding RNAs and microRNAs in cardiac hypertrophy and failure. © 2015 American Heart Association, Inc.

Mayer S.C.,Albert Ludwigs University of Freiburg | Gilsbach R.,Albert Ludwigs University of Freiburg | Preissl S.,Albert Ludwigs University of Freiburg | Monroy Ordonez E.B.,Albert Ludwigs University of Freiburg | And 28 more authors.
Circulation Research | Year: 2015

Rationale: In chronic heart failure, increased adrenergic activation contributes to structural remodeling and altered gene expression. Although adrenergic signaling alters histone modifications, it is unknown, whether it also affects other epigenetic processes, including DNA methylation and its recognition. Objective: The aim of this study was to identify the mechanism of regulation of the methyl-CpG-binding protein 2 (MeCP2) and its functional significance during cardiac pressure overload and unloading. Methods and Results: MeCP2 was identified as a reversibly repressed gene in mouse hearts after transverse aortic constriction and was normalized after removal of the constriction. Similarly, MeCP2 repression in human failing hearts resolved after unloading by a left ventricular assist device. The cluster miR-212/132 was upregulated after transverse aortic constriction or on activation of α1-and β1-adrenoceptors and miR-212/132 led to repression of MeCP2. Prevention of MeCP2 repression by a cardiomyocyte-specific, doxycycline-regulatable transgenic mouse model aggravated cardiac hypertrophy, fibrosis, and contractile dysfunction after transverse aortic constriction. Ablation of MeCP2 in cardiomyocytes facilitated recovery of failing hearts after reversible transverse aortic constriction. Genome-wide expression analysis, chromatin immunoprecipitation experiments, and DNA methylation analysis identified mitochondrial genes and their transcriptional regulators as MeCP2 target genes. Coincident with its repression, MeCP2 was removed from its target genes, whereas DNA methylation of MeCP2 target genes remained stable during pressure overload. Conclusions: These data connect adrenergic activation with a microRNA-MeCP2 epigenetic pathway that is important for cardiac adaptation during the development and recovery from heart failure. © 2015 The Authors.

Lorenzen J.M.,Hannover Medical School | Thum T.,Institute of Molecular and Translational Therapeutic Strategies IMTTS
Nature Reviews Nephrology | Year: 2016

Transcription of a large part of the human genome results in RNA transcripts that have limited or no protein-coding potential. These include long noncoding RNAs (lncRNAs), which are defined as being ≥200 nucleotides long. Unlike microRNAs, which have been extensively studied, little is known about the functional role of lncRNAs. However, studies over the past 5 years have shown that lncRNAs interfere with tissue homeostasis and have a role in pathological processes, including in the kidney and heart. The developmental expression of the microRNA sponge H19, for example, is altered in the kidneys of embryos carried by hyperglycaemic mothers, and the lncRNA Malat1 regulates hyperglycaemia-induced inflammation in endothelial cells. Putative roles for other lncRNAs have been identified in conditions such as heart failure, cardiac autophagy, hypertension, acute kidney injury, glomerular diseases, acute allograft rejection and renal cell carcinoma. This Review outlines our current understanding of the role and function of lncRNAs in kidney and cardiovascular disease as novel important regulators and potential therapeutic entry points of disease progression. © 2016 Macmillan Publishers Limited.

Lorenzen J.M.,Institute of Molecular and Translational Therapeutic Strategies IMTTS | Lorenzen J.M.,Hannover Medical School | Kumarswamy R.,Institute of Molecular and Translational Therapeutic Strategies IMTTS | Dangwal S.,Institute of Molecular and Translational Therapeutic Strategies IMTTS | And 2 more authors.
RNA Biology | Year: 2012

Diabetes mellitus due to its high prevalence and associated complications is a major socioeconomic health problem. Diabetes is characterized by multiple macro- and microvascular complications (e.g., diabetic nephropathy, cardiomyopathy, neuropathy, retinopathy). Research efforts aim to elucidate pathophysiological mechanisms contributing to the disease process. MicroRNAs are endogenous small single stranded molecules regulating targets through mRNA cleavage or translational inhibition. MicroRNAs regulate many biological cellular functions and are often deregulated during diseases. The aim of the present article is to summarize the current knowledge of the impact of microRNAs on the development of diabetes and its associated complications including endothelial and vascular smooth muscle cell dysfunction, diabetic cardiomyopathy, diabetic nephropathy, regulation of pancreatic β cell function as well as skeletal muscle and hepatic involvement. © 2012 Landes Bioscience.

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