ZIP8 induces monocyte adhesion to the aortas ex-vivo by regulating zinc influx

Cheng, Gong; Chang, Feng-Jun; You, Penghua; Lin, Jing; Huang, Xiaoyan; Wu, Haoyu; Li, Yan; Deng, Jiajun; You, Hongjun; Sun, Chaofeng

doi:10.1016/j.intimp.2018.06.018

Cited by 6 publications

(6 citation statements)

References 43 publications

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“…Analysis of the transcriptome in monocytes revealed candidate genes that could easily have been missed by expression-phenotype association analysis alone. Note that this study in human monocytes [56] is consistent with the earlier findings reported in mouse Zn-deficient monocytes that exhibit enhanced adhesion to aorta ex vivo [40] [vide supra].…”

Section: Slc39a8 Clinical Studiessupporting

confidence: 90%

“…Because Zn homeostasis is known to participate in monocyte adhesion and recruitment, expression levels of mouse Zn transporters in “non-adhering” vs “adhering” monocytes were compared. After screening expression levels of all 14 Slc39a -encoding Zn importers and all ten Slc30a -encoding Zn efflux transporters—Zn-dependent Slc39a8 was shown to be the only transporter upregulated in monocytes that adhered to aorta ex vivo [40]; however, this increase was only 2-fold. Although Slc39a8 overexpression was demonstrated to increase uptake of Zn, Fe, and Cd in monocytes, only Zn supplementation of endothelial monolayers in cell culture was confirmed to be accountable for enhancing adhesion of monocytes to endothelial cells.…”

Section: Early Mouse Slc39a8 Studiesmentioning

confidence: 99%

“…Although Slc39a8 overexpression was demonstrated to increase uptake of Zn, Fe, and Cd in monocytes, only Zn supplementation of endothelial monolayers in cell culture was confirmed to be accountable for enhancing adhesion of monocytes to endothelial cells. In Apoe ( − / − ) knockout mice fed a “Western high-fat diet,” Zn-dependent Slc39a8 upregulation was even more strongly associated with increased monocyte adhesion and recruitment to nascent atherosclerotic lesions [40].…”

Section: Early Mouse Slc39a8 Studiesmentioning

confidence: 99%

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SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside

Nebert

Liu

2019

Hum Genomics

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SLC39A8 is an evolutionarily highly conserved gene that encodes the ZIP8 metal cation transporter in all vertebrates. SLC39A8 is ubiquitously expressed, including pluripotent embryonic stem cells; SLC39A8 expression occurs in every cell type examined. Uptake of ZIP8-mediated Mn2+, Zn2+, Fe2+, Se4+, and Co2+ represents endogenous functions—moving these cations into the cell. By way of mouse genetic differences, the phenotype of “subcutaneous cadmium-induced testicular necrosis” was assigned to the Cdm locus in the 1970s. This led to identification of the mouse Slc39a8 gene, its most closely related Slc39a14 gene, and creation of Slc39a8-overexpressing, Slc39a8(neo/neo) knockdown, and cell type-specific conditional knockout mouse lines; the Slc39a8(−/−) global knockout mouse is early-embryolethal. Slc39a8(neo/neo) hypomorphs die between gestational day 16.5 and postnatal day 1—exhibiting severe anemia, dysregulated hematopoiesis, hypoplastic spleen, dysorganogenesis, stunted growth, and hypomorphic limbs. Not surprisingly, genome-wide association studies subsequently revealed human SLC39A8-deficiency variants exhibiting striking pleiotropy—defects correlated with clinical disorders in virtually every organ, tissue, and cell-type: numerous developmental and congenital disorders, the immune system, cardiovascular system, kidney, lung, liver, coagulation system, central nervous system, musculoskeletal system, eye, and gastrointestinal tract. Traits with which SLC39A8-deficiency variants are currently associated include Mn2+-deficient hypoglycosylation; numerous birth defects; Leigh syndrome-like mitochondrial redox deficiency; decreased serum high-density lipoprotein-cholesterol levels; increased body mass index; greater risk of coronary artery disease, hypotension, cardiovascular death, allergy, ischemic stroke, schizophrenia, Parkinson disease, inflammatory bowel disease, Crohn disease, myopia, and adolescent idiopathic scoliosis; systemic lupus erythematosus with primary Sjögren syndrome; decreased height; and inadvertent participation in the inflammatory progression of osteoarthritis.

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Section: Slc39a8 Clinical Studiessupporting

confidence: 90%

Section: Early Mouse Slc39a8 Studiesmentioning

confidence: 99%

Section: Early Mouse Slc39a8 Studiesmentioning

confidence: 99%

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SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside

Nebert

Liu

2019

Hum Genomics

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“…ZIP8 may contribute to the suppression of Pb-induced inflammatory responses during atherosclerosis progression. Howev-er, there are reports suggesting that ZIP8 is a precipitating factor in inflammatory changes (Melia et al, 2019;Cheng et al, 2018). Thus, further studies are required to clarify the physiological and pathological roles of ZIP8 in the initiation and progression of atherosclerosis induced by heavy metals.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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“…Studies also found that dietary zinc supplementation significantly reduced total cholesterol accumulation in the aorta and inhibit the development of aortic atherogenesis in HFD-fed New Zealand rabbits [ 193 , 194 , 195 , 196 ]. A recent study conducted by Cheng et al [ 197 ] suggests the role of zinc influx in monocyte adhesion and recruitment. Ex vivo and AEKO mice model experiments confirmed ZIP8 overexpression and increased zinc influx in monocyte adhesion to aortas and nascent atherosclerosis lesions, which potentially promote the inflammatory response towards arterial walls.…”

Section: Zinc and Atherosclerosis: Animal And Human Studiesmentioning

confidence: 99%

Investigating the Role of Zinc in Atherosclerosis: A Review

et al. 2022

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Zinc, an indispensable micronutrient for human health, might play an important role in the development of atherosclerosis. Zinc could be involved in the atherogenic process through interaction with atherogenic cells, such as endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and immune cells. In addition, zinc also exerts important positive or negative functions in various atherosclerosis-related risk factors, including lipid metabolism, glucose metabolism, and blood pressure. Currently, evidence focusing on the relationship between zinc status and atherogenic risk factors has been well established, while the direct interaction between zinc and atherosclerosis has not been fully understood. In this review, we aimed to summarize the association between zinc and atherosclerosis and explore current findings on how zinc and zinc homeostasis-associated proteins act in the atherogenic processes.

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ZIP8 induces monocyte adhesion to the aortas ex-vivo by regulating zinc influx

Cited by 6 publications

References 43 publications

SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside

SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside

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

Investigating the Role of Zinc in Atherosclerosis: A Review

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