Work

Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification

Year: 2010

Type: article

Abstract: 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.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.0912585107

Authors: Jun Wang, Elzbieta Klysik, Subeena Sood, Randy L. Johnson, Xander H. T. Wehrens, James F. Martin

Institutions: Texas A&M Health Science Center, Baylor College of Medicine, The University of Texas MD Anderson Cancer Center

Language: English

Topic: Cardiac electrophysiology and arrhythmias

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Heart, Lung, and Blood Institute, National Institute of Dental and Craniofacial Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development