7-Ketocholesterol and cholesterol-5α,6α-epoxide induce smooth muscle cell migration and proliferation through the epidermal growth factor receptor/phosphoinositide 3-kinase/Akt signaling pathways

Po Lin Liao, Yu Wen Cheng, Ching Hao Li, Yan Ting Wang, Jaw Jou Kang

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14 Citations (Scopus)

Abstract

Oxysterols, the major components of oxidized low-density lipoproteins (ox-LDLs), are present in atherosclerotic plaque and are suggested to play an active role in plaque development. The formation of an atherosclerotic lesion occurs through activation of cellular events that include vascular smooth muscle cell (SMC) migration and proliferation. Therefore, we investigated the roles of two common oxysterols, 7-ketocholesterol (7-keto) and cholesterol-5α,6α-epoxide (α-epoxide) on SMCs. Our results showed that 7-keto and α-epoxide promoted SMC migration by a chemotactic assay, and induced mitogenic effects by MTT assay and BrdU assay. Specific inhibitors confirmed that MMPs, EGFR and PI3K are involved in oxysterol-induced SMC migration, while EGFR, ERK, Akt, and sphingomyelin/ceramide pathways might play a role in SMC proliferation. More, the co-immunoprecipitation study indicated that 7-keto and α-epoxide caused EGFR phosphorylation and there was an interaction between EGFR and PI3K. At protein expression level, Akt and ERK were activated, at messenger RNA level, MMP-2/9 mRNA was transcribed, at enzyme activity level, the MMP-2/9 enzyme activity were increased in SMCs treated with 7-keto and α-epoxide according to Western bolt, RT-PCR and a fluorogenic substrate. Taken together, we concluded that 7-keto and α-epoxide may be an atherogenic factor by stimulating SMC migration and proliferation.

Original languageEnglish
Pages (from-to)88-96
Number of pages9
JournalToxicology Letters
Volume197
Issue number2
DOIs
Publication statusPublished - Aug 2010

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1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Epidermal Growth Factor Receptor
Smooth Muscle Myocytes
Cell Movement
Epoxy Compounds
Muscle
Phosphotransferases
Cells
Cell Proliferation
Assays
Enzyme activity
Matrix Metalloproteinases
Phosphatidylinositol 3-Kinases
Messenger RNA
Phosphorylation
Matrix Metalloproteinase Inhibitors
Sphingomyelins
Ceramides
Cell proliferation

Keywords

  • Atherosclerosis
  • Epidermal growth factor receptor
  • Oxysterols
  • Smooth muscle cell

ASJC Scopus subject areas

  • Toxicology

Cite this

@article{c5ff543777cf4413818b7539e89f23b6,
title = "7-Ketocholesterol and cholesterol-5α,6α-epoxide induce smooth muscle cell migration and proliferation through the epidermal growth factor receptor/phosphoinositide 3-kinase/Akt signaling pathways",
abstract = "Oxysterols, the major components of oxidized low-density lipoproteins (ox-LDLs), are present in atherosclerotic plaque and are suggested to play an active role in plaque development. The formation of an atherosclerotic lesion occurs through activation of cellular events that include vascular smooth muscle cell (SMC) migration and proliferation. Therefore, we investigated the roles of two common oxysterols, 7-ketocholesterol (7-keto) and cholesterol-5α,6α-epoxide (α-epoxide) on SMCs. Our results showed that 7-keto and α-epoxide promoted SMC migration by a chemotactic assay, and induced mitogenic effects by MTT assay and BrdU assay. Specific inhibitors confirmed that MMPs, EGFR and PI3K are involved in oxysterol-induced SMC migration, while EGFR, ERK, Akt, and sphingomyelin/ceramide pathways might play a role in SMC proliferation. More, the co-immunoprecipitation study indicated that 7-keto and α-epoxide caused EGFR phosphorylation and there was an interaction between EGFR and PI3K. At protein expression level, Akt and ERK were activated, at messenger RNA level, MMP-2/9 mRNA was transcribed, at enzyme activity level, the MMP-2/9 enzyme activity were increased in SMCs treated with 7-keto and α-epoxide according to Western bolt, RT-PCR and a fluorogenic substrate. Taken together, we concluded that 7-keto and α-epoxide may be an atherogenic factor by stimulating SMC migration and proliferation.",
keywords = "Atherosclerosis, Epidermal growth factor receptor, Oxysterols, Smooth muscle cell",
author = "Liao, {Po Lin} and Cheng, {Yu Wen} and Li, {Ching Hao} and Wang, {Yan Ting} and Kang, {Jaw Jou}",
year = "2010",
month = "8",
doi = "10.1016/j.toxlet.2010.05.002",
language = "English",
volume = "197",
pages = "88--96",
journal = "Toxicology Letters",
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T1 - 7-Ketocholesterol and cholesterol-5α,6α-epoxide induce smooth muscle cell migration and proliferation through the epidermal growth factor receptor/phosphoinositide 3-kinase/Akt signaling pathways

AU - Liao, Po Lin

AU - Cheng, Yu Wen

AU - Li, Ching Hao

AU - Wang, Yan Ting

AU - Kang, Jaw Jou

PY - 2010/8

Y1 - 2010/8

N2 - Oxysterols, the major components of oxidized low-density lipoproteins (ox-LDLs), are present in atherosclerotic plaque and are suggested to play an active role in plaque development. The formation of an atherosclerotic lesion occurs through activation of cellular events that include vascular smooth muscle cell (SMC) migration and proliferation. Therefore, we investigated the roles of two common oxysterols, 7-ketocholesterol (7-keto) and cholesterol-5α,6α-epoxide (α-epoxide) on SMCs. Our results showed that 7-keto and α-epoxide promoted SMC migration by a chemotactic assay, and induced mitogenic effects by MTT assay and BrdU assay. Specific inhibitors confirmed that MMPs, EGFR and PI3K are involved in oxysterol-induced SMC migration, while EGFR, ERK, Akt, and sphingomyelin/ceramide pathways might play a role in SMC proliferation. More, the co-immunoprecipitation study indicated that 7-keto and α-epoxide caused EGFR phosphorylation and there was an interaction between EGFR and PI3K. At protein expression level, Akt and ERK were activated, at messenger RNA level, MMP-2/9 mRNA was transcribed, at enzyme activity level, the MMP-2/9 enzyme activity were increased in SMCs treated with 7-keto and α-epoxide according to Western bolt, RT-PCR and a fluorogenic substrate. Taken together, we concluded that 7-keto and α-epoxide may be an atherogenic factor by stimulating SMC migration and proliferation.

AB - Oxysterols, the major components of oxidized low-density lipoproteins (ox-LDLs), are present in atherosclerotic plaque and are suggested to play an active role in plaque development. The formation of an atherosclerotic lesion occurs through activation of cellular events that include vascular smooth muscle cell (SMC) migration and proliferation. Therefore, we investigated the roles of two common oxysterols, 7-ketocholesterol (7-keto) and cholesterol-5α,6α-epoxide (α-epoxide) on SMCs. Our results showed that 7-keto and α-epoxide promoted SMC migration by a chemotactic assay, and induced mitogenic effects by MTT assay and BrdU assay. Specific inhibitors confirmed that MMPs, EGFR and PI3K are involved in oxysterol-induced SMC migration, while EGFR, ERK, Akt, and sphingomyelin/ceramide pathways might play a role in SMC proliferation. More, the co-immunoprecipitation study indicated that 7-keto and α-epoxide caused EGFR phosphorylation and there was an interaction between EGFR and PI3K. At protein expression level, Akt and ERK were activated, at messenger RNA level, MMP-2/9 mRNA was transcribed, at enzyme activity level, the MMP-2/9 enzyme activity were increased in SMCs treated with 7-keto and α-epoxide according to Western bolt, RT-PCR and a fluorogenic substrate. Taken together, we concluded that 7-keto and α-epoxide may be an atherogenic factor by stimulating SMC migration and proliferation.

KW - Atherosclerosis

KW - Epidermal growth factor receptor

KW - Oxysterols

KW - Smooth muscle cell

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