Pérez-Hernández Marta, Matamoros Marcos, Barana Adriana, Amorós Irene, Gómez Ricardo, Núñez Mercedes, Sacristán Sandra, Pinto Ángel, Fernández-Avilés Francisco, Tamargo Juan, Delpón Eva, Caballero Ricardo
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.
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.
Cardiovasc Res. 2016 Mar 1;109(3):431-41. doi: 10.1093/cvr/cvv280. Epub 2015 Dec 28.
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.
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.
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.
心房颤动（AF）会使心房的电特性迅速改变（电重构），从而促使其自身复发。在慢性房颤（CAF）患者中，缓慢延迟整流钾电流（IKs）上调和电压门控钙电流（ICa,L）下调是电重构的标志，并且对动作电位时程和心房不应期的缩短起关键作用。最近有证据表明，Pitx2c是一种参与指导心脏不对称形态发生的类双胸同源域转录因子，可能在心房重构中发挥作用。然而，其对IKs和ICa,L的影响尚不清楚。
实时定量聚合酶链反应分析表明，CAF患者的人心房肌细胞中Pitx2c mRNA表达显著高于窦性心律患者。Pitx2c的表达分别与IKs和ICa,L密度呈正相关和负相关。Pitx2c在HL-1细胞中的表达增加了IKs密度并降低了ICa,L密度。荧光素酶测定表明，Pitx2c增加了KCNQ1和KCNE1基因的转录活性。相反，其对ICa,L的影响可能由心房利钠肽介导。
我们的结果首次证明，CAF会增加分离的人心房肌细胞中Pitx2c的表达，并表明这种转录因子可能导致人类中观察到的CAF诱导的IKs增加和ICa,L降低。
