Zinc transporters and cardiac pathophysiology

Zinc, an essential trace element, is critical for maintaining the normal cardiac structure and function by regulating oxidative stress, mitochondrial homeostasis, and intracellular signaling pathways. Zinc homeostasis is maintained by a tightly coordinated network of zinc transporters and zinc-responsive sensors. Zinc transporters are classified into two functionally opposing families: the SLC39A/ZIP family imports zinc into the cytosol, whereas the SLC30A/ZnT family promotes zinc efflux from the cytosol. Dys-expression or dys-functions of these transporters is implicated in the pathology of various cardiovascular diseases, including ischemia/reperfusion (I/R) injury, diabetic cardiomyopathy (DCM)), hypertrophy, and atrial fibrillation. Key transporters such as ZIP2, ZIP7, ZIP8, ZIP13, ZIP14, ZnT1, and ZnT5 perform distinct and context-dependent functions in cardiac physiology and pathpysiology. In addition, zinc-responsive sensors such as PIAS3 sense fluctuations in intracellular free zinc levels and rapidly trigger adaptive transcriptional programs that modulate expression of zinc transporters to restore zinc homeostasis. This review summarizes current advances in the understanding of zinc dyshomeostasis in cardiac pathophysiology, and highlights the emerging roles of zinc transporters as potential modulators and therapeutic targets in cardiovascular diseases.