Journal ArticleDOI
MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts
Thomas Thum,Carina Gross,Jan Fiedler,Thomas Fischer,Stephan Kissler,Markus Bussen,Paolo Galuppo,Steffen Just,Wolfgang Rottbauer,Stefan Frantz,Mirco Castoldi,Jürgen Soutschek,Victor Koteliansky,Andreas Rosenwald,M. Albert Basson,Jonathan D. Licht,John T. R. Pena,Sara H. Rouhanifard,Martina U. Muckenthaler,Thomas Tuschl,Gail R. Martin,Johann Bauersachs,Stefan Engelhardt,Stefan Engelhardt +23 more
TLDR
It is shown that microRNA-21 regulates the ERK–MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function and confirms miR-21 as a disease target in heart failure and establishes the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.Abstract:
MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Dysregulation of microRNAs by several mechanisms has been described in various disease states including cardiac disease. Whereas previous studies of cardiac disease have focused on microRNAs that are primarily expressed in cardiomyocytes, the role of microRNAs expressed in other cell types of the heart is unclear. Here we show that microRNA-21 (miR-21, also known as Mirn21) regulates the ERK-MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function. miR-21 levels are increased selectively in fibroblasts of the failing heart, augmenting ERK-MAP kinase activity through inhibition of sprouty homologue 1 (Spry1). This mechanism regulates fibroblast survival and growth factor secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy. In vivo silencing of miR-21 by a specific antagomir in a mouse pressure-overload-induced disease model reduces cardiac ERK-MAP kinase activity, inhibits interstitial fibrosis and attenuates cardiac dysfunction. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibroblasts. Our results validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.read more
Citations
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Journal ArticleDOI
A YAP/TAZ-miR-130/301 molecular circuit exerts systems-level control of fibrosis in a network of human diseases and physiologic conditions
Thomas Bertero,Katherine A. Cottrill,Sofia Annis,Balkrishen Bhat,Bernadette R. Gochuico,Juan C. Osorio,Ivan O. Rosas,Kathleen J. Haley,Kathleen E. Corey,Raymond T. Chung,B. Nelson Chau,Stephen Y. Chan +11 more
TL;DR: In two diseases (pulmonary fibrosis and liver fibrosis), inhibition of microRNA-130/301 prevented the induction of ECM modification, YAP/TAZ, and downstream tissue fibrosis, suggesting mechanical forces act through a central feedback circuit to sustain a common fibrotic phenotype across a network of human physiology and pathophysiologic states.
Journal ArticleDOI
Integrative analysis of miRNA and mRNA paired expression profiling of primary fibroblast derived from diabetic foot ulcers reveals multiple impaired cellular functions.
Liang Liang,Rivka C. Stone,Olivera Stojadinovic,Horacio Ramirez,Horacio Ramirez,Irena Pastar,Anna G. Maione,Avi Smith,Vanessa Yanez,Aristides Veves,Robert S. Kirsner,Jonathan A. Garlick,Marjana Tomic-Canic +12 more
TL;DR: Induction ofmiR‐21‐5p, miR‐34a‐ 5p,MiR‐145‐5P in DFU dermal fibroblasts plays an important role in impairing multiple cellular functions, thus contributing to overall inhibition of healing in DFUs.
Journal ArticleDOI
Emerging Roles for MicroRNAs in Perioperative Medicine
TL;DR: The present review highlights the important biological functions of miRNAs and their usefulness as perioperative biomarkers and discusses the pharmacologic approaches that modulate miRNA functions for disease treatment.
Journal ArticleDOI
MiR-21 protected against diabetic cardiomyopathy induced diastolic dysfunction by targeting gelsolin.
TL;DR: Findings reveal a new role of miR-21 in attenuating diabetic cardiomyopathy by targeting gelsolin, and provide a molecular basis for developing a miRNA-based therapy against diabetic carduomyopathy.
Journal ArticleDOI
Diabetic Cardiomyopathy: Current Approach and Potential Diagnostic and Therapeutic Targets
Georgiana-Emmanuela Gilca,Gabriela Stefanescu,Oana Viola Badulescu,Daniela Maria Tanase,Iris Bararu,Manuela Ciocoiu +5 more
TL;DR: Since a strategy for prevention and treatment in order to improve the prognosis of DCM has not been established, it is important to identify clear pathophysiological landmarks, to pinpoint the available diagnostic possibilities and to spot potential therapeutic targets.
References
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Journal ArticleDOI
MicroRNAs: Genomics, Biogenesis, Mechanism, and Function
TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.
Journal ArticleDOI
The functions of animal microRNAs
TL;DR: Evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.
Journal ArticleDOI
Silencing of microRNAs in vivo with ‘antagomirs’
Jan Krützfeldt,Nikolaus Rajewsky,Ravi Braich,Kallanthottathil G. Rajeev,Thomas Tuschl,Muthiah Manoharan,Markus Stoffel +6 more
TL;DR: It is shown that a novel class of chemically engineered oligonucleotides, termed ‘antagomirs’, are efficient and specific silencers of endogenous miRNA levels in mice and may represent a therapeutic strategy for silencing miRNAs in disease.
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A synthetic inhibitor of the mitogen-activated protein kinase cascade.
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Journal ArticleDOI
A microRNA component of the p53 tumour suppressor network
Lin He,Xingyue He,Xingyue He,Lee P. Lim,Elisa de Stanchina,Elisa de Stanchina,Zhenyu Xuan,Yu Liang,Wen Xue,Lars Zender,Jill F. Magnus,Dana Ridzon,Aimee L. Jackson,Peter S. Linsley,Caifu Chen,Scott W. Lowe,Michele A. Cleary,Gregory J. Hannon +17 more
TL;DR: A family of miRNAs, miR-34a–c, whose expression reflected p53 status is described, whose encoded genes are direct transcriptional targets of p53, whose induction by DNA damage and oncogenic stress depends on p53 both in vitro and in vivo.
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