PMID- 34681906
OWN - NLM
STAT- MEDLINE
DCOM- 20211215
LR  - 20231213
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 20
DP  - 2021 Oct 18
TI  - Sarcomeres Morphology and Z-Line Arrangement Disarray Induced by Ventricular 
      Premature Contractions through the Rac2/Cofilin Pathway.
LID - 10.3390/ijms222011244 [doi]
LID - 11244
AB  - The most common ventricular premature contractions (VPCs) originate from the 
      right ventricular outflow tract (RVOT), but the molecular mechanisms of altered 
      cytoskeletons of VPC-induced cardiomyopathy remain unexplored. We created a RVOT 
      bigeminy VPC pig model (n = 6 in each group). Echocardiography was performed. The 
      histopathological alternations in the LV myocardium were analyzed, and next 
      generation sequencing (NGS) and functional enrichment analyses were employed to 
      identify the differentially expressed genes (DEGs) responsible for the 
      histopathological alternations. Finally, a cell silencing model was used to 
      confirm the key regulatory gene and pathway. VPC pigs had increased LV diameters 
      in the 6-month follow-up period. A histological study showed more actin 
      cytoskeleton disorganization and actin accumulation over intercalated disc, 
      Z-line arrangement disarray, increased beta-catenin expression, and cardiomyocyte 
      enlargement in the LV myocardium of the VPC pigs compared to the control pigs. 
      The NGS study showed actin cytoskeleton signaling, RhoGDI signaling, and 
      signaling by Rho Family GTPases and ILK Signaling presented z-scores with same 
      activation states. The expressions of Rac family small GTPase 2 (Rac2), the 
      p-cofilin/cofilin ratio, and the F-actin/G-actin ratio were downregulated in the 
      VPC group compared to the control group. Moreover, the intensity and number of 
      actin filaments per cardiomyocyte were significantly decreased by Rac2 siRNA in 
      the cell silencing model. Therefore, the Rac2/cofilin pathway was found to play a 
      crucial role in the sarcomere morphology and Z-line arrangement disarray induced 
      by RVOT bigeminy VPCs.
FAU - Lin, Yu-Sheng
AU  - Lin YS
AUID- ORCID: 0000-0001-9706-4534
AD  - Division of Cardiology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
AD  - Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung 
      University, Taoyuan 33305, Taiwan.
FAU - Chang, Tzu-Hao
AU  - Chang TH
AUID- ORCID: 0000-0001-7011-3754
AD  - Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei 
      11031, Taiwan.
FAU - Ho, Wan-Chun
AU  - Ho WC
AD  - Division of Cardiology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
FAU - Chang, Shun-Fu
AU  - Chang SF
AUID- ORCID: 0000-0002-2276-7785
AD  - Department of Medical Research and Development, Chiayi Chang Gung Memorial 
      Hospital, Chiayi 61363, Taiwan.
FAU - Chen, Yung-Lung
AU  - Chen YL
AUID- ORCID: 0000-0001-7465-0880
AD  - Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung 
      Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, 
      Taiwan.
FAU - Chang, Shih-Tai
AU  - Chang ST
AUID- ORCID: 0000-0003-1485-0893
AD  - Division of Cardiology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
FAU - Chen, Huang-Chung
AU  - Chen HC
AD  - Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung 
      Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, 
      Taiwan.
FAU - Pan, Kuo-Li
AU  - Pan KL
AUID- ORCID: 0000-0001-5418-9724
AD  - Division of Cardiology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
FAU - Chen, Mien-Cheng
AU  - Chen MC
AUID- ORCID: 0000-0002-3184-4404
AD  - Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung 
      Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, 
      Taiwan.
LA  - eng
GR  - NMRPG8F6081, NMRPG8F6082, NMRPG8F6083/Chiayi Chang Gung Memorial Hospital/
GR  - MOST 105-2314-B-182A-101-MY3, 106-2314-B-182A-092, 107-2314-B-182A-161/Ministry 
      of Science and Technology/
PT  - Journal Article
DEP - 20211018
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Actin Depolymerizing Factors)
RN  - EC 3.6.5.2 (rac GTP-Binding Proteins)
SB  - IM
MH  - Actin Cytoskeleton/metabolism/*pathology
MH  - Actin Depolymerizing Factors/genetics/*metabolism
MH  - Animals
MH  - Arrhythmias, Cardiac/metabolism/*pathology
MH  - Heart Ventricles/metabolism/*pathology
MH  - Male
MH  - Sarcomeres/metabolism/*pathology
MH  - Swine
MH  - Swine, Miniature
MH  - rac GTP-Binding Proteins/genetics/*metabolism
MH  - RAC2 GTP-Binding Protein
PMC - PMC8541677
OTO - NOTNLM
OT  - Rac2/cofilin
OT  - actin cytoskeleton signaling
OT  - cardiomyopathy
OT  - sarcomere
OT  - ventricular premature contraction
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript; or in the decision to publish the results.
EDAT- 2021/10/24 06:00
MHDA- 2021/12/16 06:00
PMCR- 2021/10/18
CRDT- 2021/10/23 01:09
PHST- 2021/09/12 00:00 [received]
PHST- 2021/10/11 00:00 [revised]
PHST- 2021/10/12 00:00 [accepted]
PHST- 2021/10/23 01:09 [entrez]
PHST- 2021/10/24 06:00 [pubmed]
PHST- 2021/12/16 06:00 [medline]
PHST- 2021/10/18 00:00 [pmc-release]
AID - ijms222011244 [pii]
AID - ijms-22-11244 [pii]
AID - 10.3390/ijms222011244 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Oct 18;22(20):11244. doi: 10.3390/ijms222011244.