Marta Pérez-Hernández1, Marcos Matamoros1, Adriana Barana1, Irene Amorós1, Ricardo Gómez1, Mercedes Núñez1, Sandra Sacristán1, Ángel Pinto2, Francisco Fernández-Avilés2, Juan Tamargo1, Eva Delpón3, Ricardo Caballero1. 1. Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain. 2. Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid 28007, Spain. 3. Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain edelpon@med.ucm.es.
Abstract
AIMS: Atrial fibrillation (AF) produces rapid changes in the electrical properties of the atria (electrical remodelling) that promote its own recurrence. In chronic AF (CAF) patients, up-regulation of the slow delayed rectifier K(+) current (IKs) and down-regulation of the voltage-gated Ca(2+) current (ICa,L) are hallmarks of electrical remodelling and critically contribute to the abbreviation of action potential duration and atrial refractory period. Recent evidences suggested that Pitx2c, a bicoid-related homeodomain transcription factor involved in directing cardiac asymmetric morphogenesis, could play a role in atrial remodelling. However, its effects on IKs and ICa,L are unknown. METHODS AND RESULTS: Real-time quantitative polymerase chain reaction analysis showed that Pitx2c mRNA expression was significantly higher in human atrial myocytes from CAF patients than those from sinus rhythm patients. The expression of Pitx2c was positively and negatively correlated with IKs and ICa,L densities, respectively. Expression of Pitx2c in HL-1 cells increased IKs density and reduced ICa,L density. Luciferase assays demonstrated that Pitx2c increased transcriptional activity of KCNQ1 and KCNE1 genes. Conversely, its effects on ICa,L could be mediated by the atrial natriuretic peptide. CONCLUSION: Our results demonstrated for the first time that CAF increases Pitx2c expression in isolated human atrial myocytes and suggested that this transcription factor could contribute to the CAF-induced IKs increase and ICa,L reduction observed in humans. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Atrial fibrillation (AF) produces rapid changes in the electrical properties of the atria (electrical remodelling) that promote its own recurrence. In chronic AF (CAF) patients, up-regulation of the slow delayed rectifier K(+) current (IKs) and down-regulation of the voltage-gated Ca(2+) current (ICa,L) are hallmarks of electrical remodelling and critically contribute to the abbreviation of action potential duration and atrial refractory period. Recent evidences suggested that Pitx2c, a bicoid-related homeodomain transcription factor involved in directing cardiac asymmetric morphogenesis, could play a role in atrial remodelling. However, its effects on IKs and ICa,L are unknown. METHODS AND RESULTS: Real-time quantitative polymerase chain reaction analysis showed that Pitx2c mRNA expression was significantly higher in human atrial myocytes from CAF patients than those from sinus rhythm patients. The expression of Pitx2c was positively and negatively correlated with IKs and ICa,L densities, respectively. Expression of Pitx2c in HL-1 cells increased IKs density and reduced ICa,L density. Luciferase assays demonstrated that Pitx2c increased transcriptional activity of KCNQ1 and KCNE1 genes. Conversely, its effects on ICa,L could be mediated by the atrial natriuretic peptide. CONCLUSION: Our results demonstrated for the first time that CAF increases Pitx2c expression in isolated human atrial myocytes and suggested that this transcription factor could contribute to the CAF-induced IKs increase and ICa,L reduction observed in humans. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Ricardo Caballero; Raquel G Utrilla; Irene Amorós; Marcos Matamoros; Marta Pérez-Hernández; David Tinaquero; Silvia Alfayate; Paloma Nieto-Marín; Guadalupe Guerrero-Serna; Qing-Hua Liu; Roberto Ramos-Mondragón; Daniela Ponce-Balbuena; Todd Herron; Katherine F Campbell; David Filgueiras-Rama; Rafael Peinado; José L López-Sendón; José Jalife; Eva Delpón; Juan Tamargo Journal: Proc Natl Acad Sci U S A Date: 2017-01-03 Impact factor: 11.205