title: Lead induces dysregulation of iron regulatory protein 1 via the extracellular signal-regulated kinase pathway in human vascular endothelial cells.
abstract: Lead (Pb) can target the vascular system for both acute injury and disease promotion. Cellular iron (Fe) disruption may be implicated in Pb vascular toxicity. To investigate the potential involvement of iron response element 1 (IRP1) protein in the vascular endothelium during Pb exposure, human umbilical vein endothelial cells (HUVEC) were treated with different concentrations of lead nitrate, 30 μM iron sulfate, or 100 μM deferoxamine. PD98059, a specific inhibitor of the mitogen-activated protein kinase kinase (MEK) activator, was administered to block the ERK/MAPK pathway. Western blotting was used to detect the expression of IRP1 and p-ERK1/2, and microscopy, and co-immunoprecipitation was used to show the association between IRP1 and p-ERK1/2. In vitro measurements revealed a decrease in IRP1 and activated ERK1/2 in the membrane following Pb treatment. HUVEC treated with PD98059 enhanced the levels of membrane IRP1 and efficiently inhibited the effect of Pb on the levels of membrane IRP1. Partial IRP1 co-localization existed with p-ERK1/2 in the membrane, and Pb treatment produced an obvious decrease in the amount of IRP1 that co-localized with p-ERK1/2. Co-immunoprecipitation further revealed a possible association between IRP-1 and p-ERK1/2. Collectively, Pb specifically induced the dysregulation of IRP1 protein by activating the ERK1/2 signaling pathway in the plasma membrane, indicating a novel role for IRP1 and the ERK/MAPK pathway in vascular endothelial functions.
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Wenbin
authors.initials: W
authors.lastname: Zhang
authors.forename: Mingchao
authors.initials: M
authors.lastname: Liu
authors.forename: Yaoming
authors.initials: Y
authors.lastname: Chen
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Chen
authors.forename: Wenjing
authors.initials: W
authors.lastname: Luo
mesh_terms: D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D015386:Hazardous Substances / Q000633:toxicity; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D035941:Iron Regulatory Protein 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007854:Lead / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D009566:Nitrates / Q000633:toxicity*
chemical_list: D015386:Hazardous Substances; D009566:Nitrates; D007854:Lead; C017461:lead nitrate; C546175:ACO1 protein, human; D035941:Iron Regulatory Protein 1