Blockade of Fibroblast YAP Attenuates Cardiac Fibrosis and Dysfunction Through MRTF-A Inhibition

[Display omitted] •YAP is activated by myocardial infarction or neuroendocrine stimulation in cardiac fibroblasts.•Active YAP promotes TEA domain transcription factor-1–mediated transcription of myocardin-related transcription factor A to facilitate cardiac myofibroblast differentiation and extracel...

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Bibliographic Details
Published in:JACC. Basic to translational science Vol. 5; no. 9; pp. 931 - 945
Main Authors: Francisco, Jamie, Zhang, Yu, Jeong, Jae Im, Mizushima, Wataru, Ikeda, Shohei, Ivessa, Andreas, Oka, Shinichi, Zhai, Peiyong, Tallquist, Michelle D., Del Re, Dominic P.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.09.2020
Elsevier
Subjects:
cardiac fibrosis
Cardiovascular
heart failure
Hippo signaling
myocardial infarction
Preclinical Research
YAP
heart failure
Hippo signaling
NRCF
MRTF-A
SMA
myocardial infarction
Mkl1
YAP
mRNA
TGF
TEAD
cardiac fibrosis
PE
MCM
PDGFR
MI
AngII
myocardin-related transcription factor A
neonatal rat cardiac fibroblast
Mer-Cre-Mer
phenylephrine
platelet-derived growth factor receptor
messenger ribonucleic acid
yes-associated protein
megakaryoblastic leukemia 1
TEA domain transcription factor
angiotensin II
transforming growth factor
smooth muscle actin
NRCF, neonatal rat cardiac fibroblast
MRTF-A, myocardin-related transcription factor A
Mkl1, megakaryoblastic leukemia 1
YAP, yes-associated protein
MI, myocardial infarction
PDGFR, platelet-derived growth factor receptor
SMA, smooth muscle actin
TGF, transforming growth factor
MCM, Mer-Cre-Mer
PE, phenylephrine
AngII, angiotensin II
TEAD, TEA domain transcription factor
mRNA, messenger ribonucleic acid
ISSN:2452-302X, 2452-302X
Online Access:Get full text
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Summary:[Display omitted] •YAP is activated by myocardial infarction or neuroendocrine stimulation in cardiac fibroblasts.•Active YAP promotes TEA domain transcription factor-1–mediated transcription of myocardin-related transcription factor A to facilitate cardiac myofibroblast differentiation and extracellular matrix gene expression.•Cardiac fibroblast YAP knockout mice have attenuated cardiac fibrosis and dysfunction in response to myocardial infarction. Fibrotic remodeling of the heart in response to injury contributes to heart failure, yet therapies to treat fibrosis remain elusive. Yes-associated protein (YAP) is activated in cardiac fibroblasts by myocardial infarction, and genetic inhibition of fibroblast YAP attenuates myocardial infarction–induced cardiac dysfunction and fibrosis. YAP promotes myofibroblast differentiation and associated extracellular matrix gene expression through engagement of TEA domain transcription factor 1 and subsequent de novo expression of myocardin-related transcription factor A. Thus, fibroblast YAP is a promising therapeutic target to prevent fibrotic remodeling and heart failure.
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ISSN:2452-302X
2452-302X
DOI:10.1016/j.jacbts.2020.07.009