A Brief Overview from the Physiological and Detrimental Roles of Zinc Homeostasis via Zinc Transporters in the Heart.

Zinc (mostly as free/labile Zn) is an essential structural constituent of many proteins, including enzymes in cellular signaling pathways via functioning as an important signaling molecule in mammalian cells. In cardiomyocytes at resting condition, intracellular labile Zn concentration ([Zn]) is in the nanomolar range, whereas it can increase dramatically under pathological conditions, including hyperglycemia, but the mechanisms that affect its subcellular redistribution is not clear. Therefore, overall, very little is known about the precise mechanisms controlling the intracellular distribution of labile Zn, particularly via Zn transporters during cardiac function under both physiological and pathophysiological conditions. Literature data demonstrated that [Zn] homeostasis in mammalian cells is primarily coordinated by Zn transporters classified as ZnTs (SLC30A) and ZIPs (SLC39A). To identify the molecular mechanisms of diverse functions of labile Zn in the heart, the recent studies focused on the discovery of subcellular localization of these Zn transporters in parallel to the discovery of novel physiological functions of [Zn] in cardiomyocytes. The present review summarizes the current understanding of the role of [Zn] changes in cardiomyocytes under pathological conditions, and under high [Zn] and how Zn transporters are important for its subcellular redistribution. The emerging importance and the promise of some Zn transporters for targeted cardiac therapy against pathological stimuli are also provided. Taken together, the review clearly outlines cellular control of cytosolic Zn signaling by Zn transporters, the role of Zn transporters in heart function under hyperglycemia, the role of Zn under increased oxidative stress and ER stress, and their roles in cancer are discussed.