The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis
Por:
Herraiz-Martinez, A, Llach, A, Tarifa, C, Gandia, J, Jimenez-Sabado, V, Lozano-Velasco, E, Serra, SA, Vallmitjana, A, de Castroviejo, EVR, Benitez, R, Aranega, A, Munoz-Guijosa, C, Franco, D, Cinca, J, Hove-Madsen, L
Publicada:
1 mar 2019
Resumen:
Aims Single nucleotide polymorphisms on chromosome 4q25 have been associated with risk of atrial fibrillation (AF) but the exiguous knowledge of the mechanistic links between these risk variants and underlying electrophysiological alterations hampers their clinical utility. Here, we tested the hypothesis that 4q25 risk variants cause alterations in the intracellular calcium homoeostasis that predispose to spontaneous electrical activity.
Methods and results Western blotting, confocal calcium imaging, and patch-clamp techniques were used to identify mechanisms linking and the 4q25 risk variants rs2200733T and rs13143308T to defects in the calcium homoeostasis in human atrial myocytes. Our findings revealed that the rs13143308T variant was more frequent in patients with AF and that myocytes from carriers of this variant had a significantly higher density of calcium sparks (14.1 +/- 4.5 vs. 3.1 +/- 1.3 events/min, P=0.02), frequency of transient inward currents (/(T1))(1.33 +/- 0.24 vs. 0.26 +/- 0.09 events/min, P<0.001) and incidence of spontaneous membrane depolarizations (1.22 +/- 0.26 vs. 0.56 +/- 0.17 events/min, P=0.001) than myocytes from patients with the normal rs13143308G variant. These alterations were linked to higher sarcoplasmic reticulum calcium loading (10.2 +/- 1.4 vs. 7.3 +/- 0.5 amol/pF, P= 0.01), SERCA2 expression (1.37 +/- 0.13 fold, P= 0.03), and RyR2 phosphorylation at ser2808 (0.67 +/- 0.08 vs. 0.47 +/- 0.03, P=0.01) but not at ser2814 (0.28 +/- 0.14 vs. 0.31 +/- 0.14, P=0.61) in patients carrying the rs13143308T risk variant. Furthermore, the presence of a risk variant or AF independently increased the /(T1) frequency and the increase in the /(T1) frequency observed in carriers of the risk variants was exacerbated in those with AF. By contrast, the presence of a risk variant did not affect the amplitude or properties of the L-type calcium current in patients with or without AF.
Conclusions Here, we identify the 4q25 variant rs13143308T as a genetic risk marker for AF, specifically associated with excessive calcium release and spontaneous electrical activity linked to increased SERCA2 expression and RyR2 phosphorylation.
Filiaciones:
Herraiz-Martinez, A:
IIBB Antiguo Hosp Santa Creu & Sant Pau, CSIC, Biomed Res Inst Barcelona, 11 St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, IIB Sant Pau, Barcelona, Spain
Llach, A:
Hosp Santa Creu & Sant Pau, IIB Sant Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Cardiol, Barcelona, Spain
Tarifa, C:
IIBB Antiguo Hosp Santa Creu & Sant Pau, CSIC, Biomed Res Inst Barcelona, 11 St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, IIB Sant Pau, Barcelona, Spain
Gandia, J:
IIBB Antiguo Hosp Santa Creu & Sant Pau, CSIC, Biomed Res Inst Barcelona, 11 St Antoni Ma Claret 167, Barcelona 08025, Spain
Jimenez-Sabado, V:
CiberCV, Madrid, Spain
Lozano-Velasco, E:
Univ Jaen, Dept Expt Biol, Jean, Spain
Serra, SA:
IIBB Antiguo Hosp Santa Creu & Sant Pau, CSIC, Biomed Res Inst Barcelona, 11 St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, IIB Sant Pau, Barcelona, Spain
Vallmitjana, A:
Univ Politecn Cataluna, Dept Automat Control, Barcelona, Spain
de Castroviejo, EVR:
Reg Hosp Ciudad Jaen Spain, Cardiol Unit, Jean, Spain
Benitez, R:
Univ Politecn Cataluna, Dept Automat Control, Barcelona, Spain
Aranega, A:
Univ Jaen, Dept Expt Biol, Jean, Spain
Munoz-Guijosa, C:
Hosp Santa Creu & Sant Pau, Dept Cardiac Surg, Barcelona, Spain
Franco, D:
Univ Jaen, Dept Expt Biol, Jean, Spain
Cinca, J:
Hosp Santa Creu & Sant Pau, IIB Sant Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Cardiol, Barcelona, Spain
CiberCV, Madrid, Spain
Hove-Madsen, L:
IIBB Antiguo Hosp Santa Creu & Sant Pau, CSIC, Biomed Res Inst Barcelona, 11 St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, IIB Sant Pau, Barcelona, Spain
CiberCV, Madrid, Spain
Green Published, Hybrid Gold
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