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
The therapeutic potential of miRNAs regulated in settings of physiological cardiac hypertrophy.
TL;DR: Information on miRNAs regulated in models of physiological hypertrophy is presented, preclinical cardiac disease studies that have successfully targeted miRN as regulated in settings of physiological growth are described, and challenges to overcome for the safe entry of miRNA-based therapies into the clinic for heart failure patients are discussed.
Journal ArticleDOI
Small and long non-coding RNAs in cardiac homeostasis and regeneration.
TL;DR: In this article, the biological roles of microRNAs and long non-coding RNAs are discussed, with a particular emphasis on their known and putative roles in cardiac homeostasis and regeneration.
Journal ArticleDOI
The role of microRNAs in heart failure
Hongjiang Wang,Jun Cai +1 more
TL;DR: A review of studies focused upon the target genes and functionality of miRNAs in the pathophysiological processes of heart failure provides an overview of current understanding of the roles of mi RNAs in cardiovascular health and diseases.
Journal ArticleDOI
Circulating microRNA-21 is an early predictor of ROS-mediated damage in subjects with high risk of developing diabetes and in drug-naïve T2D
Lucia La Sala,Simona Mrakic-Sposta,Elena Tagliabue,Francesco Prattichizzo,Stefano Micheloni,Elena Sangalli,Claudia Specchia,Anna Chiara Uccellatore,Silvia Lupini,Gaia Spinetti,Paola de Candia,Antonio Ceriello +11 more
TL;DR: The data demonstrate that microRNA-21 is associated with prediabetic status and exhibits predictive value for early detection of glucose imbalances, and could provide novel clues for miR-based biomarkers to evaluate diabetes.
Journal ArticleDOI
Cardiac fibroblast-specific p38α MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin-6 signaling mechanism.
Sumia A. Bageghni,Karen E Hemmings,Ngonidzashe Zava,Christopher P. Denton,Karen E. Porter,Justin F. X. Ainscough,Mark J. Drinkhill,Neil A. Turner +7 more
TL;DR: Cardiac fibroblast‐specific p38α MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin‐6 signaling mechanism, and in vitro mechanistic studies determined that cardiac fibroblasts responded to damaged myocardium by secreting severalParacrine factors known to induce cardiomyocyte hypertropy, including IL‐6, whose secretion was dependent upon p38 α activity.
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.
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Jan Krützfeldt,Nikolaus Rajewsky,Ravi Braich,Kallanthottathil G. Rajeev,Thomas Tuschl,Muthiah Manoharan,Markus Stoffel +6 more
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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
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Alessandra Carè,Daniele Catalucci,Federica Felicetti,Désirée Bonci,Antonio Addario,Paolo Gallo,Marie Louise Bang,Patrizia Segnalini,Yusu Gu,Nancy D. Dalton,Leonardo Elia,Michael V.G. Latronico,Morten A. Høydal,Camillo Autore,Matteo Antonio Russo,Gerald W. Dorn,Øyvind Ellingsen,Pilar Ruiz-Lozano,Kirk L. Peterson,Carlo M. Croce,Cesare Peschle,Gianluigi Condorelli +21 more