Cytosolic increased labile Zn contributes to arrhythmogenic action potentials in left ventricular cardiomyocytes through protein thiol oxidation and cellular ATP depletion.

Intracellular labile (free) Zn-level ([Zn]) is low and increases markedly under pathophysiological conditions in cardiomyocytes. High [Zn] is associated with alterations in excitability and ionic-conductances while exact mechanisms are not clarified yet. Therefore, we examined the elevated-[Zn] on some sarcolemmal ionic-mechanisms, which can mediate cardiomyocyte dysfunction. High-[Zn] induced significant changes in action potential (AP) parameters, including depolarization in resting membrane-potential and prolongations in AP-repolarizing phases. We detected also the time-dependent effects such as induction of spontaneous APs at the time of ≥ 3 min following [Zn] increases, a manner of cellular ATP dependent and reversible with disulfide-reducing agent dithiothreitol, DTT. High-[Zn] induced inhibitions in voltage-dependent K-channel currents, such as transient outward K-currents, I, steady-state currents, I and inward-rectifier K-currents, I, reversible with DTT seemed to be responsible from the prolongations in APs. We, for the first time, demonstrated that lowering cellular ATP level induced significant decreaeses in both I and I, while no effect on I. However, the increased-[Zn] could induce marked activation in ATP-sensitive K-channel currents, I, depending on low cellular ATP and thiol-oxidation levels of these channels. The mRNA levels of Kv4.3, Kv1.4 and Kv2.1 were depressed markedly with increased-[Zn] with no change in mRNA level of Kv4.2, while the mRNA level of I subunit, SUR2A was increased significantly with increased-[Zn], being reversible with DTT. Overall we demonstrated that high-[Zn] even if nanomolar levels, alters cardiac function via prolonged APs of cardiomyocytes, at most, due to inhibitions in voltage-dependent K-currents, although activation of I is playing cardioprotective role, through some biochemical changes in cellular ATP- and thiol-oxidation levels. It seems, a well-controlled [Zn] can be novel therapeutic target for cardiac complications under pathological conditions including oxidative stress.