title: Pitx2c increases in atrial myocytes from chronic atrial fibrillation patients enhancing IKs and decreasing ICa,L.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Marta
authors.initials: M
authors.lastname: Pérez-Hernández
authors.affiliation: 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.
authors.forename: Marcos
authors.initials: M
authors.lastname: Matamoros
authors.affiliation: 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.
authors.forename: Adriana
authors.initials: A
authors.lastname: Barana
authors.affiliation: 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.
authors.forename: Irene
authors.initials: I
authors.lastname: Amorós
authors.affiliation: 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.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gómez
authors.affiliation: 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.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Núñez
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sacristán
authors.affiliation: 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.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Pinto
authors.affiliation: 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.
authors.forename: Francisco
authors.initials: F
authors.lastname: Fernández-Avilés
authors.affiliation: 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.
authors.forename: Juan
authors.initials: J
authors.lastname: Tamargo
authors.affiliation: 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.
authors.forename: Eva
authors.initials: E
authors.lastname: Delpón
authors.affiliation: 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.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Caballero
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D015536:Down-Regulation; D006325:Heart Atria / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D011188:Potassium / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation; D000097577:Homeobox Protein PITX2
chemical_list: D002118:Calcium; D018398:Homeodomain Proteins; D011188:Potassium; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2
keywords: Chronic atrial fibrillation; Human atrial myocytes; ICa,L; IKs; Pitx2c