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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CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress.
Carolin Lerchenmüller,Carolin Lerchenmüller,Charles P Rabolli,Ashish Yeri,Robert R. Kitchen,Ane M. Salvador,Laura Liu,Olivia Ziegler,Kirsty Danielson,Colin Platt,Ravi V. Shah,Federico Damilano,Piyusha Kundu,Eva Riechert,Hugo A. Katus,Jeffrey E. Saffitz,Hasmik Keshishian,Steve Carr,Vassilios J. Bezzerides,Saumya Das,Anthony Rosenzweig +20 more
TL;DR: CITED4 protects against pathological cardiac remodeling by regulating mTOR activity and a network of miRNAs mediating cardiomyocyte to fibroblast crosstalk and highlighting the importance of CITED4 in response to both physiological and pathological stimuli.
Journal ArticleDOI
Non-genomic Effects of Estrogen on Cell Homeostasis and Remodeling With Special Focus on Cardiac Ischemia/Reperfusion Injury.
Rossella Puglisi,Gianfranco Mattia,Alessandra Carè,Giuseppe Marano,Walter Malorni,Paola Matarrese +5 more
TL;DR: This review takes into consideration the main mechanisms involved in cellular remodeling following an ischemic injury, with special focus on the possible role played by non-genomic estrogen effects, and a role for estrogen in this sex disparity has been hypothesized.
Journal ArticleDOI
The role of epigenetics in the fibrotic processes associated with glaucoma.
TL;DR: Evidence suggests that a hypoxic environment in glaucoma may induce aberrant epigenetic mechanisms that contribute to disease fibrosis, and these may prove to be relevant therapeutic targets in glAUcoma.
Journal ArticleDOI
Implication of microRNAs in atrial natriuretic peptide and nitric oxide signaling in vascular smooth muscle cells
TL;DR: The present results implicate miRs in NO and ANP signaling in general and miR-21 in particular in cGMP signaling and vascular smooth muscle cell relaxation.
Journal ArticleDOI
FARNA: knowledgebase of inferred functions of non-coding RNA transcripts.
Tanvir Alam,Mahmut Uludag,Magbubah Essack,Adil Salhi,Haitham Ashoor,John B. Hanks,Craig Kapfer,Katsuhiko Mineta,Takashi Gojobori,Vladimir B. Bajic +9 more
TL;DR: FARNA, having the most comprehensive function annotation of considered ncRNAs across widest spectrum of human cells/tissues, has a potential to greatly contribute to the understanding of ncRNA roles and their regulatory mechanisms in human.
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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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