Impact of Labile Zinc on Heart Function: From Physiology to Pathophysiology

Zinc plays an important role in biological systems as bound and histochemically reactive labile Zn(2+). Although Zn(2+) concentration is in the nM range in cardiomyocytes at rest and increases dramatically under stimulation, very little is known about precise mechanisms controlling the intracellular distribution of Zn(2+) and its variations during cardiac function. Recent studies are focused on molecular and cellular aspects of labile Zn(2+) and its homeostasis in mammalian cells and growing evidence clarified the molecular mechanisms underlying Zn(2+)-diverse functions in the heart, leading to the discovery of novel physiological functions of labile Zn(2+) in parallel to the discovery of subcellular localization of Zn(2+)-transporters in cardiomyocytes. Additionally, important experimental data suggest a central role of intracellular labile Zn(2+) in excitation-contraction coupling in cardiomyocytes by shaping Ca(2+) dynamics. Cellular labile Zn(2+) is tightly regulated against its adverse effects through either Zn(2+)-transporters, Zn(2+)-binding molecules or Zn(2+)-sensors, and, therefore plays a critical role in cellular signaling pathways. The present review summarizes the current understanding of the physiological role of cellular labile Zn(2+) distribution in cardiomyocytes and how a remodeling of cellular Zn(2+)-homeostasis can be important in proper cell function with Zn(2+)-transporters under hyperglycemia. We also emphasize the recent investigations on Zn(2+)-transporter functions from the standpoint of human heart health to diseases together with their clinical interest as target proteins in the heart under pathological condition, such as diabetes.