title: Disturbance of copper homeostasis is a mechanism for homocysteine-induced vascular endothelial cell injury.
abstract: Elevation of serum homocysteine (Hcy) levels is a risk factor for cardiovascular diseases. Previous studies suggested that Hcy interferes with copper (Cu) metabolism in vascular endothelial cells. The present study was undertaken to test the hypothesis that Hcy-induced disturbance of Cu homeostasis leads to endothelial cell injury. Exposure of human umbilical vein endothelial cells (HUVECs) to concentrations of Hcy at 0.01, 0.1 or 1 mM resulted in a concentration-dependent decrease in cell viability and an increase in necrotic cell death. Pretreatment of the cells with a final concentration of 5 µM Cu in cultures prevented the effects of Hcy. Hcy decreased intracellular Cu concentrations. HPLC-ICP-MS analysis revealed that Hcy caused alterations in the distribution of intracellular Cu; more Cu was redistributed to low molecular weight fractions. ESI-Q-TOF detected the formation of Cu-Hcy complexes. Hcy also decreased the protein levels of Cu chaperone COX17, which was accompanied by a decrease in the activity of cytochrome c oxidase (CCO) and a collapse of mitochondrial membrane potential. These effects of Hcy were all preventable by Cu pretreatment. The study thus demonstrated that Hcy disturbs Cu homeostasis and limits the availability of Cu to critical molecules such as COX17 and CCO, leading to mitochondrial dysfunction and endothelial cell injury.
authors.affiliation: Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Daoyin
authors.initials: D
authors.lastname: Dong
authors.forename: Biao
authors.initials: B
authors.lastname: Wang
authors.forename: Wen
authors.initials: W
authors.lastname: Yin
authors.forename: Xueqing
authors.initials: X
authors.lastname: Ding
authors.forename: Jingjing
authors.initials: J
authors.lastname: Yu
authors.forename: Y James
authors.initials: YJ
authors.lastname: Kang
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology; D000079922:Copper Transport Proteins; D003576:Electron Transport Complex IV / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects; D006710:Homocysteine / Q000009:adverse effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis
chemical_list: C491006:COX17 protein, human; D002352:Carrier Proteins; D000079922:Copper Transport Proteins; D006710:Homocysteine; D003300:Copper; D003576:Electron Transport Complex IV