Document Detail


Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification.
MedLine Citation:
PMID:  20457925     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, often coexists with the related arrhythmia atrial flutter (AFL). Limitations in effectiveness and safety of current therapies make an understanding of the molecular mechanism underlying AF more urgent. Genome-wide association studies implicated a region of human chromosome 4q25 in familial AF and AFL, approximately 150 kb distal to the Pitx2 homeobox gene, a developmental left-right asymmetry (LRA) gene. To investigate the significance of the 4q25 variants, we used mouse models to investigate Pitx2 in atrial arrhythmogenesis directly. When challenged by programmed stimulation, Pitx2(null+/-) adult mice had atrial arrhythmias, including AFL and atrial tachycardia, indicating that Pitx2 haploinsufficiency predisposes to atrial arrhythmias. Microarray and in situ studies indicated that Pitx2 suppresses sinoatrial node (SAN)-specific gene expression, including Shox2, in the left atrium of embryos and young adults. In vivo ChIP and transfection experiments indicated that Pitx2 directly bound Shox2 in vivo, supporting the notion that Pitx2 directly inhibits the SAN-specific genetic program in left atrium. Our findings implicate Pitx2 and Pitx2-mediated LRA-signaling pathways in prevention of atrial arrhythmias.
Authors:
Jun Wang; Elzbieta Klysik; Subeena Sood; Randy L Johnson; Xander H T Wehrens; James F Martin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-05-10
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-26     Completed Date:  2010-06-29     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9753-8     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Arrhythmias, Cardiac / genetics,  metabolism*,  pathology*,  physiopathology
Atrial Fibrillation / genetics,  metabolism,  pathology
Base Sequence
Disease Susceptibility
Electrocardiography
Gene Expression Regulation
Homeodomain Proteins / metabolism*
Humans
Mice
Mice, Knockout
Sequence Alignment
Signal Transduction
Transcription Factors / deficiency,  metabolism*
Grant Support
ID/Acronym/Agency:
2R01DE/HD12324-12/DE/NIDCR NIH HHS; R01 HL089598/HL/NHLBI NIH HHS; R01 HL089598-03/HL/NHLBI NIH HHS; R01DE16329/DE/NIDCR NIH HHS; R01HD052785/HD/NICHD NIH HHS; R01HL089598/HL/NHLBI NIH HHS; R01HL091947/HL/NHLBI NIH HHS; R01HL093484-01/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Homeodomain Proteins; 0/Shox2 protein, mouse; 0/Transcription Factors; 184787-43-7/homeobox protein PITX2
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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