Role of CaMKII in post acidosis arrhythmias: A simulation study using a human myocyte model.

LASCANO EC, SAID M, VITTONE L, MATTIAZZI A, MUNDIÑA-WEILENMANN C, NEGRONI JÁ.; LASCANO EC, SAID M, VITTONE L, MATTIAZZI A, MUNDIÑA-WEILENMANN C, NEGRONI JÁ.

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY

ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD

Lugar: Manchester; Año: 2013 vol. 60 p. 172 - 183

0022-2828

Postacidotic arrhythmias have been associated to increased sarcoplasmic reticulum (SR) Ca2+ load and Ca2+/ calmodulin-dependent protein kinase II (CaMKII) activation. However, the molecular mechanisms underlying these arrhythmias are still unclear. To better understand this process, acidosis produced by CO2 increase from 5% to 30%, resulting in intracellular pH (pHi) change from 7.15 to 6.7, was incorporated into a myocyte model of excitation-contraction coupling and contractility, including acidotic inhibition of L-type Ca2+ channel (ICaL), Na+–Ca2+ exchanger, Ca2+ release through the SR ryanodine receptor (RyR2) (Irel), Ca2+ reuptake by the SR Ca2+ ATPase2a (Iup), Na+–K+ pump, K+ efflux through the inward rectifier K+ channel and the transient outward K+ flow (Ito) together with increased activity of the Na+–H+ exchanger (INHE). Simulated CaMKII regulation affecting Irel, Iup, ICaL, INHE and Ito was introduced in the model to partially compensate the acidosis outcome. Late Na+ current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca2+ leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.2+ load and Ca2+/ calmodulin-dependent protein kinase II (CaMKII) activation. However, the molecular mechanisms underlying these arrhythmias are still unclear. To better understand this process, acidosis produced by CO2 increase from 5% to 30%, resulting in intracellular pH (pHi) change from 7.15 to 6.7, was incorporated into a myocyte model of excitation-contraction coupling and contractility, including acidotic inhibition of L-type Ca2+ channel (ICaL), Na+–Ca2+ exchanger, Ca2+ release through the SR ryanodine receptor (RyR2) (Irel), Ca2+ reuptake by the SR Ca2+ ATPase2a (Iup), Na+–K+ pump, K+ efflux through the inward rectifier K+ channel and the transient outward K+ flow (Ito) together with increased activity of the Na+–H+ exchanger (INHE). Simulated CaMKII regulation affecting Irel, Iup, ICaL, INHE and Ito was introduced in the model to partially compensate the acidosis outcome. Late Na+ current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca2+ leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.2 increase from 5% to 30%, resulting in intracellular pH (pHi) change from 7.15 to 6.7, was incorporated into a myocyte model of excitation-contraction coupling and contractility, including acidotic inhibition of L-type Ca2+ channel (ICaL), Na+–Ca2+ exchanger, Ca2+ release through the SR ryanodine receptor (RyR2) (Irel), Ca2+ reuptake by the SR Ca2+ ATPase2a (Iup), Na+–K+ pump, K+ efflux through the inward rectifier K+ channel and the transient outward K+ flow (Ito) together with increased activity of the Na+–H+ exchanger (INHE). Simulated CaMKII regulation affecting Irel, Iup, ICaL, INHE and Ito was introduced in the model to partially compensate the acidosis outcome. Late Na+ current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca2+ leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.i) change from 7.15 to 6.7, was incorporated into a myocyte model of excitation-contraction coupling and contractility, including acidotic inhibition of L-type Ca2+ channel (ICaL), Na+–Ca2+ exchanger, Ca2+ release through the SR ryanodine receptor (RyR2) (Irel), Ca2+ reuptake by the SR Ca2+ ATPase2a (Iup), Na+–K+ pump, K+ efflux through the inward rectifier K+ channel and the transient outward K+ flow (Ito) together with increased activity of the Na+–H+ exchanger (INHE). Simulated CaMKII regulation affecting Irel, Iup, ICaL, INHE and Ito was introduced in the model to partially compensate the acidosis outcome. Late Na+ current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca2+ leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.2+ channel (ICaL), Na+–Ca2+ exchanger, Ca2+ release through the SR ryanodine receptor (RyR2) (Irel), Ca2+ reuptake by the SR Ca2+ ATPase2a (Iup), Na+–K+ pump, K+ efflux through the inward rectifier K+ channel and the transient outward K+ flow (Ito) together with increased activity of the Na+–H+ exchanger (INHE). Simulated CaMKII regulation affecting Irel, Iup, ICaL, INHE and Ito was introduced in the model to partially compensate the acidosis outcome. Late Na+ current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca2+ leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.+–Ca2+ exchanger, Ca2+ release through the SR ryanodine receptor (RyR2) (Irel), Ca2+ reuptake by the SR Ca2+ ATPase2a (Iup), Na+–K+ pump, K+ efflux through the inward rectifier K+ channel and the transient outward K+ flow (Ito) together with increased activity of the Na+–H+ exchanger (INHE). Simulated CaMKII regulation affecting Irel, Iup, ICaL, INHE and Ito was introduced in the model to partially compensate the acidosis outcome. Late Na+ current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca2+ leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.2+ ATPase2a (Iup), Na+–K+ pump, K+ efflux through the inward rectifier K+ channel and the transient outward K+ flow (Ito) together with increased activity of the Na+–H+ exchanger (INHE). Simulated CaMKII regulation affecting Irel, Iup, ICaL, INHE and Ito was introduced in the model to partially compensate the acidosis outcome. Late Na+ current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca2+ leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.+ flow (Ito) together with increased activity of the Na+–H+ exchanger (INHE). Simulated CaMKII regulation affecting Irel, Iup, ICaL, INHE and Ito was introduced in the model to partially compensate the acidosis outcome. Late Na+ current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca2+ leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.rel, Iup, ICaL, INHE and Ito was introduced in the model to partially compensate the acidosis outcome. Late Na+ current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca2+ leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.+ current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca2+ leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.2+ leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.2+], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis.i after 6 min acidosis.