Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification.
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.
Wang
Jun
J
Institute of Biosciences and Technology, Texas A&M System Health Science Center, Houston, TX 77030, USA.
Klysik
Elzbieta
E
Sood
Subeena
S
Johnson
Randy L
RL
Wehrens
Xander H T
XH
Martin
James F
JF
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D004198:Disease Susceptibility; D004562:Electrocardiography; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016415:Sequence Alignment; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D000097577:Homeobox Protein PITX2
D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C484663:Shox2 protein, mouse
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