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
Circulating miRNAs: reflecting or affecting cardiovascular disease?
TL;DR: The findings of studies focusing on circulating microRNAs present in human blood cells or plasma/serum are summarized, where they potentially could serve as diagnostic or prognostic markers for a variety of cardiovascular pathologies, including acute myocardial infarction, heart failure, coronary artery disease, stroke, diabetes and hypertension.
Journal ArticleDOI
Diffuse myocardial fibrosis: mechanisms, diagnosis and therapeutic approaches.
Begoña López,Begoña López,Susana Ravassa,Susana Ravassa,María U. Moreno,María U. Moreno,Gorka San José,Gorka San José,Javier Beaumont,Javier Beaumont,Arantxa González,Arantxa González,Javier Díez,Javier Díez +13 more
TL;DR: Diez et al. as discussed by the authors summarized the current knowledge on the mechanisms and detrimental consequences of diffuse myocardial fibrosis in heart failure and discussed the validity and usefulness of available imaging techniques and circulating biomarkers to assess the clinicopathological variation in this lesion and to track its clinical evolution.
Journal ArticleDOI
Non-cardiomyocyte microRNAs in Heart Failure
TL;DR: This review summarizes the current insights on the role of miRNAs outside myocytes in the heart and discusses miRNA function in fibroblasts, endothelial cells and immune cells in response to myocardial stress as occurs after myocardIAL infarction and in the pathogenesis of HF.
Journal ArticleDOI
Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants
TL;DR: It is shown that the angiotensin II type 1 (AT1) receptor is locally activated in pathological and physiological cardiac hypertrophy, although with exercise training it can be stimulated independently of the involvement of angiotENSin II.
Journal ArticleDOI
The continuum of personalized cardiovascular medicine: a position paper of the European Society of Cardiology
Paulus Kirchhof,Paulus Kirchhof,Karin R. Sipido,Martin R. Cowie,Thomas Eschenhagen,Keith A.A. Fox,Hugo A. Katus,Stefan Schroeder,Heribert Schunkert,Silvia G. Priori +9 more
TL;DR: Clinical information obtained from history and physical examination, functional and imaging studies, biochemical biomarkers, genetic/epigenetic data, and pathophysiological insights into disease-driving processes need to be integrated into a new taxonomy of CVDs to allow personalized disease management.
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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