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
Non-coding RNAs in human disease
TL;DR: Dysregulation of these ncRNAs is being found to have relevance not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases, and there is great interest in therapeutic strategies to counteract these perturbations.
Journal ArticleDOI
MicroRNA therapeutics: towards a new era for the management of cancer and other diseases
TL;DR: Recent advances in the understanding of miRNAs in cancer and in other diseases are described and the challenge of identifying the most efficacious therapeutic candidates is discussed and a perspective on achieving safe and targeted delivery of miRNA therapeutics is provided.
Journal ArticleDOI
Mechanisms of fibrosis: therapeutic translation for fibrotic disease
TL;DR: How cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix–producing myofibroblasts is described.
Journal ArticleDOI
MicroRNAs in Stress Signaling and Human Disease
Joshua T. Mendell,Eric N. Olson +1 more
TL;DR: Emerging principles of miRNA regulation of stress signaling pathways are reviewed and applied to the authors' understanding of the roles of miRNAs in disease.
Journal ArticleDOI
Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches
TL;DR: This review guides the reader through important aspects of non-coding RNA biology, including their biogenesis, mode of actions, physiological function, as well as their role in the disease context (such as in cancer or the cardiovascular system).
References
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Journal ArticleDOI
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
TL;DR: The data show thatmiR-133, and possibly miR-1, are key regulators of cardiac hypertrophy, suggesting their therapeutic application in heart disease.
Journal ArticleDOI
Control of Stress-Dependent Cardiac Growth and Gene Expression by a MicroRNA
Eva van Rooij,Lillian B. Sutherland,Xiaoxia Qi,James A. Richardson,Joseph A. Hill,Eric N. Olson +5 more
TL;DR: It is found that a cardiac-specific microRNA (miR-208) encoded by an intron of the αMHC gene is required for cardiomyocyte hypertrophy, fibrosis, and expression of βMHC in response to stress and hypothyroidism.
Journal ArticleDOI
Dysregulation of Cardiogenesis, Cardiac Conduction, and Cell Cycle in Mice Lacking miRNA-1-2
Yong Zhao,Joshua F. Ransom,Ankang Li,Ankang Li,Vasanth Vedantham,Morgan von Drehle,Alecia N. Muth,Takatoshi Tsuchihashi,Michael T. McManus,Robert J. Schwartz,Deepak Srivastava +10 more
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Journal ArticleDOI
The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2.
Baofeng Yang,Huixian Lin,Huixian Lin,Huixian Lin,Jiening Xiao,Jiening Xiao,Jiening Xiao,Yanjie Lu,Xiaobin Luo,Xiaobin Luo,Xiaobin Luo,Baoxin Li,Ying Zhang,Chaoqian Xu,Yunlong Bai,Huizhen Wang,Huizhen Wang,Guohao Chen,Zhiguo Wang,Zhiguo Wang,Zhiguo Wang +20 more
TL;DR: It is shown that miR-1 is overexpression in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis and is a potential antiarrhythmic target.
Journal ArticleDOI
Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation
Gille Pages,Philippe Lenormand,Gilles L'Allemain,Jean-Claude Chambard,Sylvain Meloche,Jacques Pouysségur +5 more
TL;DR: It is demonstrated that activation of these ubiquitously expressed MAP kinases is essential for growth, and growth factor activation of p42mapk and p44mapk is an absolute requirement for triggering the proliferative response.
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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