Cytosolic increased labile Zn 2+ contributes to arrhythmogenic action potentials in left ventricular cardiomyocytes through protein thiol oxidation and cellular ATP depletion.

Intracellular labile (free) Zn2+ -level ([Zn2+ ]i ) is low and increases markedly under pathophysiological conditions in cardiomyocytes. High [Zn2+ ]i is associated with alterations in excitability and ionic-conductances while exact mechanisms are not clarified yet. Therefore, we examined the elevated-[Zn2+ ]i on some sarcolemmal ionic-mechanisms, which can mediate cardiomyocyte dysfunction. High-[Zn2+ ]i 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 [Zn2+ ]i increases, a manner of cellular ATP dependent and reversible with disulfide-reducing agent dithiothreitol, DTT. High-[Zn2+ ]i induced inhibitions in voltage-dependent K+ -channel currents, such as transient outward K+ -currents, Ito , steady-state currents, Iss and inward-rectifier K+ -currents, IK1 , 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 Iss and IK1 , while no effect on Ito . However, the increased-[Zn2+ ]i could induce marked activation in ATP-sensitive K+ -channel currents, IKATP , 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-[Zn2+ ]i with no change in mRNA level of Kv4.2, while the mRNA level of IKATP subunit, SUR2A was increased significantly with increased-[Zn2+ ]i , being reversible with DTT. Overall we demonstrated that high-[Zn2+ ]i, 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 IKATP is playing cardioprotective role, through some biochemical changes in cellular ATP- and thiol-oxidation levels. It seems, a well-controlled [Zn2+ ]i can be novel therapeutic target for cardiac complications under pathological conditions including oxidative stress.