科研之友
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Key points Intracellular [Na+] ([Na+](i)) is elevated in heart failure (HF) and causes arrhythmogenic cellular [Ca2+](i) loading. In HF, hyperactivity of Ca2+-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 Ca2+ 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 [Ca2+](i). We found that a 3-4mm gain in [Na+](i) (similar to that reported in HF) perturbs Ca2+ and membrane potential homeostasis in part via CaMKII activation. This disrupted Ca2+ homeostasis is exacerbated by CaMKII overexpression, and strongly relies upon CaMKII-Na+-Ca2+-CaMKII feedback. CaMKII inhibition in HF may be beneficial, in part by inhibiting [Na+](i) loading, and thereby normalizing Ca2+ and membrane potential dynamics without disrupting systolic function. Ca2+-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 Ca2+ ([Ca2+](i)) overload by altering the equilibrium of the Na+-Ca2+ exchanger to impair forward-mode (Ca2+ extrusion), and favour reverse-mode (Ca2+ influx) exchange. In turn, this Ca2+ overload would be expected to further activate CaMKII and thereby form a pathological positive feedback loop of ever-increasing CaMKII activity, [Na+](i), and [Ca2+](i). We developed an ionic model of the mouse ventricular myocyte to interrogate this potentially arrhythmogenic positive feedback in both control conditions and when CaMKII delta C is overexpressed as in genetically engineered mice. In control conditions, simulation of increased [Na+](i) causes the expected increases in [Ca2+](i), CaMKII activity, and target phosphorylation, which degenerate into unstable Ca2+ 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 [Ca2+](i) per se plays an important role. The effect of this CaMKII-Na+-Ca2+-CaMKII feedback is more striking in CaMKII delta C overexpression, where high [Na+](i) causes delayed afterdepolarizations, which can be prevented by imposing low [Na+](i), or clamping CaMKII phosphorylation of L-type Ca2+ channels, ryanodine receptors and phospholamban to basal levels. In this setting, Na+ loading fuels a vicious loop whereby increased CaMKII activation perturbs Ca2+ and membrane potential homeostasis. High [Na+](i) is also required to produce instability when CaMKII is further activated by increased Ca2+ loading due to beta-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 Ca2+ and membrane potential dynamics in heart failure.
- 出版日期2014-3-15
