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
Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome.
Christian Widera,Shashi Kumar Gupta,Johan M. Lorenzen,Claudia Bang,Johann Bauersachs,Kerstin Bethmann,Tibor Kempf,Kai C. Wollert,Thomas Thum +8 more
TL;DR: The present study tempers speculations about the potential usefulness of cardiomyocyte-enriched microRNAs as diagnostic or prognostic markers in ACS by assessing their diagnostic and prognostic value in a larger ACS cohort.
Journal ArticleDOI
MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca²⁺ overload and cell death.
Arin B. Aurora,Ahmed I. Mahmoud,Xiang Luo,Brett A. Johnson,Eva van Rooij,Satoshi Matsuzaki,Kenneth M. Humphries,Joseph A. Hill,Rhonda Bassel-Duby,Hesham A. Sadek,Eric N. Olson +10 more
TL;DR: A pivotal role is revealed for miR-214 as a regulator of cardiomyocyte Ca²⁺ homeostasis and survival during cardiac injury, as well as repression of several downstream effectors of Ca�⁺ signaling that mediate cell death.
Journal ArticleDOI
Identification of a microRNA signature of renal ischemia reperfusion injury
TL;DR: A molecular fingerprint of renal injury is defined and it is suggested that miR-21 may play a role in protecting TEC from death and therefore define a lymphocyte-independent signature of renal IRI.
Journal ArticleDOI
miRNAS in cardiovascular diseases: potential biomarkers, therapeutic targets and challenges
Shanshan Zhou,Jingpeng Jin,Jiqun Wang,Jiqun Wang,Zhiguo Zhang,Zhiguo Zhang,Jonathan H. Freedman,Yang Zheng,Lu Cai +8 more
TL;DR: The effects of several CVD; including heart failure, acute myocardial infarction, arrhythmias and pulmonary hypertension; on levels of circulating miRNAs are provided, as well as challenges and recommendations in their use in the diagnosis of CVD.
Journal ArticleDOI
Cardiac Fibrosis in Patients With Atrial Fibrillation: Mechanisms and Clinical Implications.
TL;DR: An overview of the general mechanisms of cardiac fibrosis in AF, differences between fibrotic processes in atria and ventricles, and the clinical and prognostic significance of cardiac fibrillation in AF is provided.
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.
Journal ArticleDOI
A synthetic inhibitor of the mitogen-activated protein kinase cascade.
TL;DR: Results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype and PD 098059 is an invaluable tool that will help elucidate the role of theMAPK cascade in a variety of biological settings.
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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