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 Zn²⁺. Although Zn²⁺ 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 Zn²⁺ and its variations during cardiac function. Recent studies are focused on molecular and cellular aspects of labile Zn²⁺ and its homeostasis in mammalian cells and growing evidence clarified the molecular mechanisms underlying Zn²⁺-diverse functions in the heart, leading to the discovery of novel physiological functions of labile Zn²⁺ in parallel to the discovery of subcellular localization of Zn²⁺-transporters in cardiomyocytes. Additionally, important experimental data suggest a central role of intracellular labile Zn²⁺ in excitation-contraction coupling in cardiomyocytes by shaping Ca²⁺ dynamics. Cellular labile Zn²⁺ is tightly regulated against its adverse effects through either Zn²⁺-transporters, Zn²⁺-binding molecules or Zn²⁺-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 Zn²⁺ distribution in cardiomyocytes and how a remodeling of cellular Zn²⁺-homeostasis can be important in proper cell function with Zn²⁺-transporters under hyperglycemia. We also emphasize the recent investigations on Zn²⁺-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.