PMID- 33264286
OWN - NLM
STAT- MEDLINE
DCOM- 20210202
LR  - 20211204
IS  - 1545-7885 (Electronic)
IS  - 1544-9173 (Print)
IS  - 1544-9173 (Linking)
VI  - 18
IP  - 12
DP  - 2020 Dec
TI  - YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing 
      and cardiac function after myocardial infarction.
PG  - e3000941
LID - 10.1371/journal.pbio.3000941 [doi]
LID - e3000941
AB  - Adverse cardiac remodeling after myocardial infarction (MI) causes structural and 
      functional changes in the heart leading to heart failure. The initial post-MI 
      pro-inflammatory response followed by reparative or anti-inflammatory response is 
      essential for minimizing the myocardial damage, healing, and scar formation. Bone 
      marrow-derived macrophages (BMDMs) are recruited to the injured myocardium and 
      are essential for cardiac repair as they can adopt both pro-inflammatory or 
      reparative phenotypes to modulate inflammatory and reparative responses, 
      respectively. Yes-associated protein (YAP) and transcriptional coactivator with 
      PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and 
      are essential for cardiac regeneration and repair. However, their functions in 
      macrophage polarization and post-MI inflammation, remodeling, and healing are not 
      well established. Here, we demonstrate that expression of YAP and TAZ is 
      increased in macrophages undergoing pro-inflammatory or reparative phenotype 
      changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and 
      enhanced reparative response. Consistently, YAP activation enhanced 
      pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote 
      pro-inflammatory response by increasing interleukin 6 (IL6) expression and impede 
      reparative response by decreasing Arginase-I (Arg1) expression through 
      interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 
      (NCoR1) repressor complex. These changes in macrophages polarization due to 
      YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased 
      angiogenesis, leading to improved cardiac function after MI. Also, YAP activation 
      augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify 
      YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or 
      reparative responses post-MI.
FAU - Mia, Masum M
AU  - Mia MM
AD  - Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School 
      Singapore. Singapore.
FAU - Cibi, Dasan Mary
AU  - Cibi DM
AD  - Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School 
      Singapore. Singapore.
FAU - Abdul Ghani, Siti Aishah Binte
AU  - Abdul Ghani SAB
AUID- ORCID: 0000-0003-2317-0179
AD  - Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School 
      Singapore. Singapore.
FAU - Song, Weihua
AU  - Song W
AD  - National Heart Research Institute Singapore, National Heart Centre Singapore, 
      Singapore.
FAU - Tee, Nicole
AU  - Tee N
AD  - National Heart Research Institute Singapore, National Heart Centre Singapore, 
      Singapore.
FAU - Ghosh, Sujoy
AU  - Ghosh S
AD  - Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School 
      Singapore. Singapore.
FAU - Mao, Junhao
AU  - Mao J
AD  - Department of Molecular, Cell and Cancer Biology, University of Massachusetts 
      Medical School, Worcester, Massachusetts, United States of America.
FAU - Olson, Eric N
AU  - Olson EN
AD  - Department of Molecular Biology, University of Texas Southwestern Medical Center, 
      Dallas, Texas, United States of America.
FAU - Singh, Manvendra K
AU  - Singh MK
AUID- ORCID: 0000-0002-2884-0074
AD  - Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School 
      Singapore. Singapore.
AD  - National Heart Research Institute Singapore, National Heart Centre Singapore, 
      Singapore.
LA  - eng
GR  - R01 DK099510/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20201202
PL  - United States
TA  - PLoS Biol
JT  - PLoS biology
JID - 101183755
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (Wwtr1 protein, mouse)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (Yap1 protein, mouse)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*metabolism/physiology
MH  - Animals
MH  - Biological Variation, Population/genetics/physiology
MH  - Cell Cycle Proteins/*metabolism/physiology
MH  - Female
MH  - Inflammation/metabolism
MH  - Macrophages/*metabolism/physiology
MH  - Male
MH  - Mice
MH  - Mice, 129 Strain
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Myocardial Infarction/metabolism/pathology
MH  - Myocardium/metabolism
MH  - Phenotype
MH  - Phosphoproteins/metabolism
MH  - Signal Transduction
MH  - Trans-Activators/*metabolism/physiology
MH  - Transcription Factors/metabolism
MH  - YAP-Signaling Proteins
PMC - PMC7735680
COIS- The authors have declared that no competing interests exist.
EDAT- 2020/12/03 06:00
MHDA- 2021/02/03 06:00
PMCR- 2020/12/02
CRDT- 2020/12/02 17:11
PHST- 2019/10/18 00:00 [received]
PHST- 2020/10/29 00:00 [accepted]
PHST- 2020/12/14 00:00 [revised]
PHST- 2020/12/03 06:00 [pubmed]
PHST- 2021/02/03 06:00 [medline]
PHST- 2020/12/02 17:11 [entrez]
PHST- 2020/12/02 00:00 [pmc-release]
AID - PBIOLOGY-D-19-03059 [pii]
AID - 10.1371/journal.pbio.3000941 [doi]
PST - epublish
SO  - PLoS Biol. 2020 Dec 2;18(12):e3000941. doi: 10.1371/journal.pbio.3000941. 
      eCollection 2020 Dec.