Functional suppression of Kcnq1 leads to early sodium channel remodelling and cardiac conduction system dysmorphogenesis
Por:
de la Rosa, AJ, Dominguez, JN, Sedmera, D, Sankova, B, Hove-Madsen, L, Franco, D, Aranega, AE
Publicada:
1 jun 2013
Resumen:
Aims Ion channel remodelling and ventricular conduction system (VCS) alterations play relevant roles in the generation of cardiac arrhythmias, but the interaction between ion channel remodelling and cardiac conduction system dysfunctions in an arrhythmogenic context remain unexplored.
Methods and results We have used a transgenic mouse line previously characterized as an animal model of Long QT Syndrome (LQTS) to analyse ion channel remodelling and VCS configuration. Reverse transcriptase-PCR and immunohistochemistry analysis showed early cardiac sodium channel upregulation at embryonic stages prior to the onset of Kv potassium channel remodelling, and cardiac hypertrophy at foetal stages. In line with these findings, patch-clamp assays demonstrated changes in sodium current density and a slowing of recovery from inactivation. Functional analysis by optical mapping revealed an immature ventricular activation pattern as well as an increase in the total left ventricle activation time in foetal transgenic hearts. Morphological analysis of LQTS transgenic mice in a Cx40(GFP/+) background demonstrated VCS dysmorphogenesis during heart development.
Conclusions Our data demonstrate early sodium channel remodelling secondary to I-Ks blockage in a mouse model of LQTS leading to morphological and functional anomalies in the developing VCS and cardiac hypertrophy. These results provide new insights into the mechanisms underlying foetal and neonatal cardiac electrophysiological disorders, which might help understand how molecular, functional, and morphological alterations are linked to clinical pathologies such as cardiac congenital anomalies, arrhythmias, and perinatal sudden death.
Filiaciones:
de la Rosa, AJ:
Univ Jaen, Fac Expt Sci, Dept Expt Biol, Jaen 23071, Spain
Acad Sci Czech Republ, Inst Physiol, Dept Cardiovasc Morphogenesis, Prague, Czech Republic
Hosp Santa Creu & Sant Pau, ICCC, CSIC, Cardiovasc Res Ctr, Barcelona, Spain
Dominguez, JN:
Univ Jaen, Fac Expt Sci, Dept Expt Biol, Jaen 23071, Spain
Acad Sci Czech Republ, Inst Physiol, Dept Cardiovasc Morphogenesis, Prague, Czech Republic
Hosp Santa Creu & Sant Pau, ICCC, CSIC, Cardiovasc Res Ctr, Barcelona, Spain
Sedmera, D:
Charles Univ Prague, Inst Anat, Fac Med 1, Prague 12800, Czech Republic
Sankova, B:
Acad Sci Czech Republ, Inst Physiol, Dept Cardiovasc Morphogenesis, Prague, Czech Republic
Hosp Santa Creu & Sant Pau, ICCC, CSIC, Cardiovasc Res Ctr, Barcelona, Spain
Hove-Madsen, L:
Acad Sci Czech Republ, Inst Physiol, Dept Cardiovasc Morphogenesis, Prague, Czech Republic
Hosp Santa Creu & Sant Pau, ICCC, CSIC, Cardiovasc Res Ctr, Barcelona, Spain
Franco, D:
Univ Jaen, Fac Expt Sci, Dept Expt Biol, Jaen 23071, Spain
Acad Sci Czech Republ, Inst Physiol, Dept Cardiovasc Morphogenesis, Prague, Czech Republic
Hosp Santa Creu & Sant Pau, ICCC, CSIC, Cardiovasc Res Ctr, Barcelona, Spain
Aranega, AE:
Univ Jaen, Fac Expt Sci, Dept Expt Biol, Jaen 23071, Spain
Acad Sci Czech Republ, Inst Physiol, Dept Cardiovasc Morphogenesis, Prague, Czech Republic
Hosp Santa Creu & Sant Pau, ICCC, CSIC, Cardiovasc Res Ctr, Barcelona, Spain
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