PITX2 Insufficiency Leads to Atrial Electrical and Structural Remodeling Linked to Arrhythmogenesis
Por:
Chinchilla, A, Daimi, H, Lozano-Velasco, E, Dominguez, JN, Caballero, R, Delpon, E, Tamargo, J, Cinca, J, Hove-Madsen, L, Aranega, AE, Franco, D
Publicada:
1 jun 2011
Resumen:
Background-Pitx2 is a homeobox transcription factor that plays a pivotal role in early left/right determination during embryonic development. Pitx2 loss-of-function mouse mutants display early embryonic lethality with severe cardiac malformations, demonstrating the importance of Pitx2 during cardiogenesis. Recently, independent genome-wide association studies have provided new evidence for a putative role of PITX2 in the adult heart. These studies have independently reported several risk variants close to the PITX2 locus on chromosome 4q25 that are strongly associated with atrial fibrillation in humans.
Methods and Results-We show for the first time that PITX2C expression is significantly decreased in human patients with sustained atrial fibrillation, thus providing a molecular link between PITX2 loss of function and atrial fibrillation. In addition, morphological, molecular, and electrophysiological characterization of chamber-specific Pitx2 conditional mouse mutants reveals that atrial but not ventricular chamber-specific deletion of Pitx2 results in differences in the action potential amplitude and resting membrane potential in the adult heart as well as ECG characteristics of atrioventricular block. Lack of Pitx2 in atrial myocardium impairs sodium channel and potassium channel expression, mediated in part by miRNA misexpression.
Conclusions-This study thus identifies Pitx2 as an upstream transcriptional regulator of atrial electric function, the insufficiency of which results in cellular and molecular changes leading to atrial electric and structural remodeling linked to arrhythmogenesis. (Circ Cardiovasc Genet. 2011; 4: 269-279.)
Filiaciones:
Chinchilla, A:
Univ Jaen, Dept Expt Biol, Jaen 23071, Spain
Daimi, H:
Univ Jaen, Dept Expt Biol, Jaen 23071, Spain
Lozano-Velasco, E:
Univ Jaen, Dept Expt Biol, Jaen 23071, Spain
Dominguez, JN:
Univ Jaen, Dept Expt Biol, Jaen 23071, Spain
Caballero, R:
Univ Complutense Madrid, Dept Pharmacol, Madrid, Spain
Delpon, E:
Univ Complutense Madrid, Dept Pharmacol, Madrid, Spain
Tamargo, J:
Univ Complutense Madrid, Dept Pharmacol, Madrid, Spain
Cinca, J:
Autonomous Univ Barcelona, Dept Cardiol, Hosp St Pau, Inst Biomed Res IBB, Barcelona, Spain
Hove-Madsen, L:
Hosp Santa Creu & Sant Pau, Cardiovasc Res Ctr CSIC ICCC, Barcelona, Spain
Aranega, AE:
Univ Jaen, Dept Expt Biol, Jaen 23071, Spain
Franco, D:
Univ Jaen, Dept Expt Biol, Jaen 23071, Spain
Bronze, Green Published
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