Cytosolic increased labile Zn2+ 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, I-to, steady-state currents, I-ss and inward-rectifier K+-currents, I-K1, 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-ss and I-K1, while no effect on I-to. However, the increased-[Zn2+](i) could induce marked activation in ATP-sensitive K+-channel currents, I-KATP, 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 I-KATP 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 I-KATP 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.