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Inhibition of profibrotic microRNA-21 affects platelets and their releasate

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Inhibition of profibrotic microRNA-21 affects platelets and their releasate. / Barwari, Temo; Eminaga, Seda; Mayr, Ursula; Lu, Ruifang; Armstrong, Paul C; Chan, Melissa V; Sahraei, Mahnaz; Fernández-Fuertes, Marta; Moreau, Thomas; Barallobre-Barreiro, Javier; Lynch, Marc; Yin, Xiaoke; Schulte, Christian; Baig, Ferheen; Pechlaner, Raimund; Langley, Sarah R; Zampetaki, Anna; Santer, Peter; Weger, Martin; Plasenzotti, Roberto; Schosserer, Markus; Grillari, Johannes; Kiechl, Stefan; Willeit, Johann; Shah, Ajay M; Ghevaert, Cedric; Warner, Timothy D; Fernández-Hernando, Carlos; Suárez, Yajaira; Mayr, Manuel.

In: JCI INSIGHT, Vol. 3, No. 21, 02.11.2018.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Barwari, T, Eminaga, S, Mayr, U, Lu, R, Armstrong, PC, Chan, MV, Sahraei, M, Fernández-Fuertes, M, Moreau, T, Barallobre-Barreiro, J, Lynch, M, Yin, X, Schulte, C, Baig, F, Pechlaner, R, Langley, SR, Zampetaki, A, Santer, P, Weger, M, Plasenzotti, R, Schosserer, M, Grillari, J, Kiechl, S, Willeit, J, Shah, AM, Ghevaert, C, Warner, TD, Fernández-Hernando, C, Suárez, Y & Mayr, M 2018, 'Inhibition of profibrotic microRNA-21 affects platelets and their releasate', JCI INSIGHT, vol. 3, no. 21. https://doi.org/10.1172/jci.insight.123335

APA

Barwari, T., Eminaga, S., Mayr, U., Lu, R., Armstrong, P. C., Chan, M. V., Sahraei, M., Fernández-Fuertes, M., Moreau, T., Barallobre-Barreiro, J., Lynch, M., Yin, X., Schulte, C., Baig, F., Pechlaner, R., Langley, S. R., Zampetaki, A., Santer, P., Weger, M., ... Mayr, M. (2018). Inhibition of profibrotic microRNA-21 affects platelets and their releasate. JCI INSIGHT, 3(21). https://doi.org/10.1172/jci.insight.123335

Vancouver

Barwari T, Eminaga S, Mayr U, Lu R, Armstrong PC, Chan MV et al. Inhibition of profibrotic microRNA-21 affects platelets and their releasate. JCI INSIGHT. 2018 Nov 2;3(21). https://doi.org/10.1172/jci.insight.123335

Bibtex

@article{18493970f0c5492ab3e026a9ff8b86c3,
title = "Inhibition of profibrotic microRNA-21 affects platelets and their releasate",
abstract = "Fibrosis is a major contributor to organ disease for which no specific therapy is available. MicroRNA-21 (miR-21) has been implicated in the fibrogenetic response, and inhibitors of miR-21 are currently undergoing clinical trials. Here, we explore how miR-21 inhibition may attenuate fibrosis using a proteomics approach. Transfection of miR-21 mimic or inhibitor in murine cardiac fibroblasts revealed limited effects on extracellular matrix (ECM) protein secretion. Similarly, miR-21-null mouse hearts showed an unaltered ECM composition. Thus, we searched for additional explanations as to how miR-21 might regulate fibrosis. In plasma samples from the community-based Bruneck Study, we found a marked correlation of miR-21 levels with several platelet-derived profibrotic factors, including TGF-β1. Pharmacological miR-21 inhibition with an antagomiR reduced the platelet release of TGF-β1 in mice. Mechanistically, Wiskott-Aldrich syndrome protein, a negative regulator of platelet TGF-β1 secretion, was identified as a direct target of miR-21. miR-21-null mice had lower platelet and leukocyte counts compared with littermate controls but higher megakaryocyte numbers in the bone marrow. Thus, to our knowledge this study reports a previously unrecognized effect of miR-21 inhibition on platelets. The effect of antagomiR-21 treatment on platelet TGF-β1 release, in particular, may contribute to the antifibrotic effects of miR-21 inhibitors.",
keywords = "Aged, Aged, 80 and over, Animals, Blood Platelets/drug effects, Clinical Trials as Topic, Extracellular Matrix/drug effects, Female, Fibroblasts/drug effects, Fibrosis/genetics, Humans, Male, Mice, Mice, Inbred C57BL/genetics, MicroRNAs/antagonists & inhibitors, Middle Aged, Myocardium/pathology, Prospective Studies, Proteomics/methods, RNA, Untranslated/genetics, Transforming Growth Factor beta1/genetics, Wiskott-Aldrich Syndrome Protein/drug effects",
author = "Temo Barwari and Seda Eminaga and Ursula Mayr and Ruifang Lu and Armstrong, {Paul C} and Chan, {Melissa V} and Mahnaz Sahraei and Marta Fern{\'a}ndez-Fuertes and Thomas Moreau and Javier Barallobre-Barreiro and Marc Lynch and Xiaoke Yin and Christian Schulte and Ferheen Baig and Raimund Pechlaner and Langley, {Sarah R} and Anna Zampetaki and Peter Santer and Martin Weger and Roberto Plasenzotti and Markus Schosserer and Johannes Grillari and Stefan Kiechl and Johann Willeit and Shah, {Ajay M} and Cedric Ghevaert and Warner, {Timothy D} and Carlos Fern{\'a}ndez-Hernando and Yajaira Su{\'a}rez and Manuel Mayr",
year = "2018",
month = nov,
day = "2",
doi = "10.1172/jci.insight.123335",
language = "English",
volume = "3",
journal = "JCI INSIGHT",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "21",

}

RIS

TY - JOUR

T1 - Inhibition of profibrotic microRNA-21 affects platelets and their releasate

AU - Barwari, Temo

AU - Eminaga, Seda

AU - Mayr, Ursula

AU - Lu, Ruifang

AU - Armstrong, Paul C

AU - Chan, Melissa V

AU - Sahraei, Mahnaz

AU - Fernández-Fuertes, Marta

AU - Moreau, Thomas

AU - Barallobre-Barreiro, Javier

AU - Lynch, Marc

AU - Yin, Xiaoke

AU - Schulte, Christian

AU - Baig, Ferheen

AU - Pechlaner, Raimund

AU - Langley, Sarah R

AU - Zampetaki, Anna

AU - Santer, Peter

AU - Weger, Martin

AU - Plasenzotti, Roberto

AU - Schosserer, Markus

AU - Grillari, Johannes

AU - Kiechl, Stefan

AU - Willeit, Johann

AU - Shah, Ajay M

AU - Ghevaert, Cedric

AU - Warner, Timothy D

AU - Fernández-Hernando, Carlos

AU - Suárez, Yajaira

AU - Mayr, Manuel

PY - 2018/11/2

Y1 - 2018/11/2

N2 - Fibrosis is a major contributor to organ disease for which no specific therapy is available. MicroRNA-21 (miR-21) has been implicated in the fibrogenetic response, and inhibitors of miR-21 are currently undergoing clinical trials. Here, we explore how miR-21 inhibition may attenuate fibrosis using a proteomics approach. Transfection of miR-21 mimic or inhibitor in murine cardiac fibroblasts revealed limited effects on extracellular matrix (ECM) protein secretion. Similarly, miR-21-null mouse hearts showed an unaltered ECM composition. Thus, we searched for additional explanations as to how miR-21 might regulate fibrosis. In plasma samples from the community-based Bruneck Study, we found a marked correlation of miR-21 levels with several platelet-derived profibrotic factors, including TGF-β1. Pharmacological miR-21 inhibition with an antagomiR reduced the platelet release of TGF-β1 in mice. Mechanistically, Wiskott-Aldrich syndrome protein, a negative regulator of platelet TGF-β1 secretion, was identified as a direct target of miR-21. miR-21-null mice had lower platelet and leukocyte counts compared with littermate controls but higher megakaryocyte numbers in the bone marrow. Thus, to our knowledge this study reports a previously unrecognized effect of miR-21 inhibition on platelets. The effect of antagomiR-21 treatment on platelet TGF-β1 release, in particular, may contribute to the antifibrotic effects of miR-21 inhibitors.

AB - Fibrosis is a major contributor to organ disease for which no specific therapy is available. MicroRNA-21 (miR-21) has been implicated in the fibrogenetic response, and inhibitors of miR-21 are currently undergoing clinical trials. Here, we explore how miR-21 inhibition may attenuate fibrosis using a proteomics approach. Transfection of miR-21 mimic or inhibitor in murine cardiac fibroblasts revealed limited effects on extracellular matrix (ECM) protein secretion. Similarly, miR-21-null mouse hearts showed an unaltered ECM composition. Thus, we searched for additional explanations as to how miR-21 might regulate fibrosis. In plasma samples from the community-based Bruneck Study, we found a marked correlation of miR-21 levels with several platelet-derived profibrotic factors, including TGF-β1. Pharmacological miR-21 inhibition with an antagomiR reduced the platelet release of TGF-β1 in mice. Mechanistically, Wiskott-Aldrich syndrome protein, a negative regulator of platelet TGF-β1 secretion, was identified as a direct target of miR-21. miR-21-null mice had lower platelet and leukocyte counts compared with littermate controls but higher megakaryocyte numbers in the bone marrow. Thus, to our knowledge this study reports a previously unrecognized effect of miR-21 inhibition on platelets. The effect of antagomiR-21 treatment on platelet TGF-β1 release, in particular, may contribute to the antifibrotic effects of miR-21 inhibitors.

KW - Aged

KW - Aged, 80 and over

KW - Animals

KW - Blood Platelets/drug effects

KW - Clinical Trials as Topic

KW - Extracellular Matrix/drug effects

KW - Female

KW - Fibroblasts/drug effects

KW - Fibrosis/genetics

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred C57BL/genetics

KW - MicroRNAs/antagonists & inhibitors

KW - Middle Aged

KW - Myocardium/pathology

KW - Prospective Studies

KW - Proteomics/methods

KW - RNA, Untranslated/genetics

KW - Transforming Growth Factor beta1/genetics

KW - Wiskott-Aldrich Syndrome Protein/drug effects

U2 - 10.1172/jci.insight.123335

DO - 10.1172/jci.insight.123335

M3 - SCORING: Journal article

C2 - 30385722

VL - 3

JO - JCI INSIGHT

JF - JCI INSIGHT

SN - 2379-3708

IS - 21

ER -