A computational model of mouse ventricular myocytes showed that a 3-4 mM gain in intracellular Na+ perturbs Ca2+ and membrane potential homeostasis via a CaMKII positive feedback loop.
Computational modeling demonstrates a synergistic, arrhythmogenic positive feedback loop between intracellular Na+ loading and CaMKII activation in heart failure, suggesting Na+ loading inhibition as a potential therapeutic target.
Key points Intracellular Na + (Na + i ) is elevated in heart failure (HF) and causes arrhythmogenic cellular Ca 2+ i loading. In HF, hyperactivity of Ca 2+ –calmodulin‐dependent protein kinase II (CaMKII), a key mediator of electrical and mechanical dysfunction in myocytes, causes elevated Na + i . We developed a computational model of mouse ventricular myocyte electrophysiology including Ca 2+ and CaMKII signalling and quantitatively confirmed evidence suggesting that not only does CaMKII cause elevated Na + i , but this additional Na + i also promotes further CaMKII activation by increasing Ca 2+ i . We found that a 3–4 m m gain in Na + i (similar to that reported in HF) perturbs Ca 2+ and membrane potential homeostasis in part via CaMKII activation. This disrupted Ca 2+ homeostasis is exacerbated by CaMKII overexpression, and strongly relies upon CaMKII–Na + –Ca 2+ –CaMKII feedback. CaMKII inhibition in HF may be beneficial, in part by inhibiting Na + i loading, and thereby normalizing Ca 2+ and membrane potential dynamics without disrupting systolic function. Abstract Ca 2+ –calmodulin‐dependent protein kinase II (CaMKII) hyperactivity in heart failure causes intracellular Na + (Na + i ) loading (at least in part by enhancing the late Na + current). This Na + i gain promotes intracellular Ca 2+ (Ca 2+ i ) overload by altering the equilibrium of the Na + –Ca 2+ exchanger to impair forward‐mode (Ca 2+ extrusion), and favour reverse‐mode (Ca 2+ influx) exchange. In turn, this Ca 2+ overload would be expected to further activate CaMKII and thereby form a pathological positive feedback loop of ever‐increasing CaMKII activity, Na + i , and Ca 2+ i . We developed an ionic model of the mouse ventricular myocyte to interrogate this potentially arrhythmogenic positive feedback in both control conditions and when CaMKIIδC is overexpressed as in genetically engineered mice. In control conditions, simulation of increased Na + i causes the expected increases in Ca 2+ i , CaMKII activity, and target phosphorylation, which degenerate into unstable Ca 2+ handling and electrophysiology at high Na + i gain. Notably, clamping CaMKII activity to basal levels ameliorates but does not completely offset this outcome, suggesting that the increase in Ca 2+ i per se plays an important role. The effect of this CaMKII–Na + –Ca 2+ –CaMKII feedback is more striking in CaMKIIδC overexpression, where high Na + i causes delayed afterdepolarizations, which can be prevented by imposing low Na + i , or clamping CaMKII phosphorylation of L‐type Ca 2+ channels, ryanodine receptors and phospholamban to basal levels. In this setting, Na + loading fuels a vicious loop whereby increased CaMKII activation perturbs Ca 2+ and membrane potential homeostasis. High Na + i is also required to produce instability when CaMKII is further activated by increased Ca 2+ loading due to β‐adrenergic activation. Our results support recent experimental findings of a synergistic interaction between perturbed Na + fluxes and CaMKII, and suggest that pharmacological inhibition of intracellular Na + loading can contribute to normalizing Ca 2+ and membrane potential dynamics in heart failure.
Morotti et al. (Tue,) conducted a other in Heart failure. Simulated increased intracellular Na+ and CaMKII overexpression vs. Control conditions was evaluated on Ca2+ and membrane potential homeostasis. A computational model of mouse ventricular myocytes showed that a 3-4 mM gain in intracellular Na+ perturbs Ca2+ and membrane potential homeostasis via a CaMKII positive feedback loop.