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
More filters
Searching for new mechanisms of myocardial fibrosis with diagnostic and/or therapeutic potential (vol 17, pg 764, 2015)
Stephane Heymans,Arantxa González,Anne Pizard,Anna-Pia Papageorgiou,Natalia López-Andrés,Frederic Jaisser,Thomas Thum,Faiez Zannad,Javier Díez +8 more
TL;DR: Molecules that stimulate the differentiation of fibroblasts into myofibroblast and subsequently alter collagen turnover and microRNA‐induced alterations of collagen gene expression are focused on.
Journal ArticleDOI
Gestational hypertension, preeclampsia and intrauterine growth restriction induce dysregulation of cardiovascular and cerebrovascular disease associated microRNAs in maternal whole peripheral blood
TL;DR: Epigenetic changes are induced by pregnancy-related complications in maternal whole peripheral blood and weak negative correlation between miR-146a-5p and MiR-221-3p expression and the pulsatility index in the umbilical artery was found.
Journal ArticleDOI
The Bcl6 target gene microRNA-21 promotes Th2 differentiation by a T cell intrinsic pathway.
TL;DR: MiR21 expression is increased in Th2-type inflammation, and the results reveal a novel T cell autonomous role for miR-21 in promoting Th2 differentiation, thus providing a new link between Bcl6 and Th2 inflammation.
Journal ArticleDOI
MiR-320a contributes to atherogenesis by augmenting multiple risk factors and down-regulating SRF
Chen Chen,Yan-Yan Wang,Shenglan Yang,Shenglan Yang,Huaping Li,Gang Zhao,Feng Wang,Lei Yang,Dao Wen Wang +8 more
TL;DR: It is shown that miR‐320a, an intergenic miRNA, is markedly elevated in the peripheral blood of coronary heart disease patients and high‐risk patients and that SP1 transcriptionally up‐regulates hsa‐miR‐ 320a expression.
Journal ArticleDOI
MicroRNAs and diabetic complications.
TL;DR: The role ofmiRNAs in the pathology of diabetic complications is explored and the potential use of miRNAs as novel diagnostic and therapeutic targets for diabetic complications are discussed.
References
More filters
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.
Related Papers (5)
MicroRNA-133 controls cardiac hypertrophy
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