Disturbance of Copper Homeostasis Is a Mechanism for Homocysteine-Induced Vascular Endothelial Cell Injury

Daoyin Dong, Biao Wang, Wen Yin, Xueqing Ding, Jingjing Yu, Yujian Kang

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere76209
JournalPLoS ONE
Volume8
Issue number10
DOIs
StatePublished - Oct 18 2013
Externally publishedYes

Fingerprint

homocysteine
Endothelial cells
Homocysteine
blood vessels
endothelial cells
Copper
homeostasis
Homeostasis
Endothelial Cells
copper
Wounds and Injuries
Electron Transport Complex IV
cytochrome-c oxidase
pretreatment
Cytochromes a
Cells
Mitochondrial Membrane Potential
Human Umbilical Vein Endothelial Cells
Cell death
membrane potential

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Disturbance of Copper Homeostasis Is a Mechanism for Homocysteine-Induced Vascular Endothelial Cell Injury. / Dong, Daoyin; Wang, Biao; Yin, Wen; Ding, Xueqing; Yu, Jingjing; Kang, Yujian.

In: PLoS ONE, Vol. 8, No. 10, e76209, 18.10.2013.

Research output: Contribution to journalArticle

Dong, Daoyin ; Wang, Biao ; Yin, Wen ; Ding, Xueqing ; Yu, Jingjing ; Kang, Yujian. / Disturbance of Copper Homeostasis Is a Mechanism for Homocysteine-Induced Vascular Endothelial Cell Injury. In: PLoS ONE. 2013 ; Vol. 8, No. 10.
@article{fab64de8931b4d7284d7a05fead2a4da,
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.",
author = "Daoyin Dong and Biao Wang and Wen Yin and Xueqing Ding and Jingjing Yu and Yujian Kang",
year = "2013",
month = "10",
day = "18",
doi = "10.1371/journal.pone.0076209",
language = "English (US)",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Disturbance of Copper Homeostasis Is a Mechanism for Homocysteine-Induced Vascular Endothelial Cell Injury

AU - Dong, Daoyin

AU - Wang, Biao

AU - Yin, Wen

AU - Ding, Xueqing

AU - Yu, Jingjing

AU - Kang, Yujian

PY - 2013/10/18

Y1 - 2013/10/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84885767233&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885767233&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0076209

DO - 10.1371/journal.pone.0076209

M3 - Article

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e76209

ER -