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Zinc plays a critical role in many physiological processes, and disruption of zinc homeostasis induces various disorders, such as growth retardation, osteopenia, immune deficiency, and inflammation. However, how the imbalance in zinc homeostasis leads to heart disease is not yet fully understood. Cardiovascular diseases are a major cause of death worldwide, and the development of novel therapeutic targets to treat it is urgently needed. We report that a zinc transporter, ZIP13, regulates cardiovascular homeostasis. We found that the expression level of Zip13 mRNA was diminished in both primary neonatal cardiomyocytes and mouse heart tissues treated with the cardiotoxic agent doxycycline. Primary neonatal cardiomyocytes from Zip13 gene-knockout (KO) mice exhibited abnormal irregular arrhythmic beating. RNA-seq analysis identified 606 differentially expressed genes in Zip13-KO mouse-derived primary neonatal cardiomyocytes and Gene ontology (GO) analysis revealed that both inflammation- and cell adhesion-related genes were significantly enriched. In addition, telemetry echocardiography analysis suggested that arrhythmias were likely to occur in Zip13-KO mice, in which elevated levels of the cardiac fibrosis marker Col1a1, vascular inflammation-related gene eNOS, and Golgi-related molecule GM130 were observed. These results indicate the physiological importance of ZIP13—it maintains cardiovascular homeostasis by resolving inflammation and stress response. Our findings suggest that optimizing ZIP13 expression and/or function may improve cardiovascular disease management.

Zinc is an essential trace element that plays an important physiological role in numerous cellular processes. Zinc deficiency can result in diverse symptoms, such as impairment of the immune response, skin disorders, and impairments in cardiovascular functions. Recent reports have demonstrated that zinc acts as a signaling molecule, and its signaling pathways, referred to as zinc signals, are related to the molecular mechanisms of cardiovascular functions. Therefore, comprehensive understanding of the significance of zinc-mediated signaling pathways is vital as a function of zinc as a nutritional component and of its molecular mechanisms and targets. Several basic and clinical studies have reported the relationship between zinc level and the onset and pathology of cardiovascular diseases, which has attracted much attention in recent years. In this review, we summarize the recent findings regarding the effects of zinc on cardiovascular function. We also discuss the importance of maintaining zinc homeostasis in the cardiovascular system and its therapeutic potential as a novel drug target.

Ehlers–Danlos syndrome spondylodysplastic type 3 (EDSSPD3, OMIM 612350) is an inherited recessive connective tissues disease caused by loss of function of SLC39A13/ZIP13, a zinc transporter belonging to the Slc39a/ZIP family. Patients with EDSSPD3 suffer from impaired development of bone and connective tissues, and muscular hypotonia, or myopathy. However, whether ZIP13 participates in the early differentiation process of these cell types remains unclear. In this study, we investigated the role of ZIP13 in myogenic differentiation using murine myoblast cell line (C2C12) as well as human patient-derived induced pluripotent stem cells (iPSCs). We found that ZIP13 expression was upregulated by myogenic stimulation in C2C12 cells, and its knockdown disrupted myotubular differentiation. Myocytes differentiated from iPSCs of patients with EDSSPD3 (EDSSPD3-iPSCs) exhibited incomplete myogenic differentiation. Moreover, the phenotypic abnormalities of EDSSPD3-iPSC-derived myocytes were corrected by genomic editing of the pathogenic ZIP13 mutation, suggesting the indispensable role of ZIP13 in myogenic differentiation. These results clearly indicate that ZIP13 is required for proper myogenic differentiation and that the study of EDSSPD3-iPSCs may help shed light on the molecular basis underlying various clinical features caused by the loss of ZIP13.

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