Lead induces a metal transporter, ZIP8, via activation of the NF-κB signaling pathway and the induction is involved in the protection against lead cytotoxicity by intracellular lead accumulation independent mechanisms in cultured vascular endothelial cells

Abstract

Lead (Pb) is an environmental pollutant that adversely affects various organs in the human body and is a well-known risk factor for cardiovascular diseases, caused by the dysfunction of vascular endothelial cells that cover the luminal surface of the blood vessels. The Zrt-and Irt-like related protein (ZIP) transporter ZIP8 is one of the primary importers of zinc, iron, manganese, and cadmium, and its expression appears to be important for the metabolism of these metals. In the present study, we investigated the influence of ZIP8 on Pb-induced cytotoxicity in vascular endothelial cells, induction of ZIP8 expression by Pb, and its mechanism of action in vascular endothelial cells. The study revealed the following: (1) Pb cytotoxicity in vascular endothelial cells was potentiated by the knockdown of ZIP8, but the intracellular accumulation of Pb in the cells remain unaffected; (2) Pb induced the expression of ZIP8;(3) the induction of ZIP8 expression by Pb was mediated by nuclear factor (NF)-κB signaling pathway; and (4) Pb activated p38, mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK), but the activation of these MAPKs was not involved in the induction of ZIP8 by Pb. Therefore, the study shows that Pb induces the expression of endothelial ZIP8 and this induction appears to be involved in the protection against Pb cytotoxicity by intracellular Pb accumulation independent mechanisms.