Antiproliferative mechanisms of raxofelast (IRFI-016) in H 2 O 2 -stimulated rat aortic smooth muscle cells

Kyung Hye Lee, So Yeon Lim, seokmin kang, Dae Hyeok Kim, Hong Keun Cho, Ji Hyung Chung, Hyuck Moon Kwon, Kwang Hoe Chung, Hakbae Lee, Yangsoo Jang, Ki Chul Hwang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Reactive oxygen species-mediated cellular injury is involved in the pathogenesis of many diseases, including those affecting the cardiovascular system, such as myocardial ischemia-reperfusion injury, inflammation, and atheroscleosis. Raxofelast (IRFI-016; (±)-5-acetoxy-2, 3-dihydro-4, 6, 7-trimethyl-2-benzofuran-acetic acid) was designed with the aim of maximizing the antioxidant potency of phenols chemically related to vitamin E. The antioxidant activity of raxofelast has been convincingly demonstrated in several in vitro studies and in various models of ischemia-reperfusion injury. In this study, the antiproliferative effects of raxofelast were investigated to determine whether transduction signals and protooncogenes are affected in H 2 O 2 -stimulated rat aortic smooth muscle cells. In a tetrazolium-based colorimetric assay, the proliferation of rat aortic smooth muscle cells was increased by 3-fold in 0.1% fetal bovine serum/Dulbecco's modified Eagle's medium (DMEM) containing 500 μM H 2 O 2 , indicating that exogenous 500 μM H 2 O 2 was a growth stimulator of rat aortic smooth muscle cells. Exogenous H 2 O 2 significantly activated extracellular signal-regulated kinases (ERKs) activity within 30 min and raxofelast inhibited the ERKs activation dose dependently in 500 μM H 2 O 2 -stimulated rat aortic smooth muscle cells (IC 50 : 200 μM). Raxofelast reduced the intracellular reactive oxygen species generated by exogenous H 2 O 2 in a dose-dependent manner. In 500 μM H 2 O 2 -stimulated rat aortic smooth muscle cells, raxofelast dramatically attenuated the activation of mitogen-activating protein kinase (MAPK)/ERK kinase 1, 2 (MEK1,2) and protein kinase C (PKC) without affecting Ras expression. Induction of c-myc mRNA was significantly reduced dose dependently up to 100 μM by raxofelast in concentrations. These data indicate that the antiproliferative effects of raxofelast in H 2 O 2 - stimulated rat aortic smooth muscle cells may involve the suppression of intracellular reactive oxygen species formation and the inhibition of ERKs by inactivation through PKC and MEK1,2 and down-regulation of c-myc expression, regardless of Ras activation.

Original languageEnglish
Pages (from-to)119-125
Number of pages7
JournalEuropean Journal of Pharmacology
Volume484
Issue number2-3
DOIs
Publication statusPublished - 2004 Jan 26

Fingerprint

Smooth Muscle Myocytes
Extracellular Signal-Regulated MAP Kinases
Reactive Oxygen Species
Reperfusion Injury
Protein Kinases
Protein Kinase C
MAP Kinase Kinase 2
Antioxidants
MAP Kinase Kinase 1
MAP Kinase Kinase Kinases
Myocardial Reperfusion Injury
Raxofelast
Eagles
Phenols
Cardiovascular System
Vitamin E
Mitogens
Acetic Acid
Myocardial Ischemia
Signal Transduction

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Lee, Kyung Hye ; Lim, So Yeon ; kang, seokmin ; Kim, Dae Hyeok ; Cho, Hong Keun ; Chung, Ji Hyung ; Kwon, Hyuck Moon ; Chung, Kwang Hoe ; Lee, Hakbae ; Jang, Yangsoo ; Hwang, Ki Chul. / Antiproliferative mechanisms of raxofelast (IRFI-016) in H 2 O 2 -stimulated rat aortic smooth muscle cells In: European Journal of Pharmacology. 2004 ; Vol. 484, No. 2-3. pp. 119-125.
@article{f05e8ed808974bd4b5c85512b19ae29b,
title = "Antiproliferative mechanisms of raxofelast (IRFI-016) in H 2 O 2 -stimulated rat aortic smooth muscle cells",
abstract = "Reactive oxygen species-mediated cellular injury is involved in the pathogenesis of many diseases, including those affecting the cardiovascular system, such as myocardial ischemia-reperfusion injury, inflammation, and atheroscleosis. Raxofelast (IRFI-016; (±)-5-acetoxy-2, 3-dihydro-4, 6, 7-trimethyl-2-benzofuran-acetic acid) was designed with the aim of maximizing the antioxidant potency of phenols chemically related to vitamin E. The antioxidant activity of raxofelast has been convincingly demonstrated in several in vitro studies and in various models of ischemia-reperfusion injury. In this study, the antiproliferative effects of raxofelast were investigated to determine whether transduction signals and protooncogenes are affected in H 2 O 2 -stimulated rat aortic smooth muscle cells. In a tetrazolium-based colorimetric assay, the proliferation of rat aortic smooth muscle cells was increased by 3-fold in 0.1{\%} fetal bovine serum/Dulbecco's modified Eagle's medium (DMEM) containing 500 μM H 2 O 2 , indicating that exogenous 500 μM H 2 O 2 was a growth stimulator of rat aortic smooth muscle cells. Exogenous H 2 O 2 significantly activated extracellular signal-regulated kinases (ERKs) activity within 30 min and raxofelast inhibited the ERKs activation dose dependently in 500 μM H 2 O 2 -stimulated rat aortic smooth muscle cells (IC 50 : 200 μM). Raxofelast reduced the intracellular reactive oxygen species generated by exogenous H 2 O 2 in a dose-dependent manner. In 500 μM H 2 O 2 -stimulated rat aortic smooth muscle cells, raxofelast dramatically attenuated the activation of mitogen-activating protein kinase (MAPK)/ERK kinase 1, 2 (MEK1,2) and protein kinase C (PKC) without affecting Ras expression. Induction of c-myc mRNA was significantly reduced dose dependently up to 100 μM by raxofelast in concentrations. These data indicate that the antiproliferative effects of raxofelast in H 2 O 2 - stimulated rat aortic smooth muscle cells may involve the suppression of intracellular reactive oxygen species formation and the inhibition of ERKs by inactivation through PKC and MEK1,2 and down-regulation of c-myc expression, regardless of Ras activation.",
author = "Lee, {Kyung Hye} and Lim, {So Yeon} and seokmin kang and Kim, {Dae Hyeok} and Cho, {Hong Keun} and Chung, {Ji Hyung} and Kwon, {Hyuck Moon} and Chung, {Kwang Hoe} and Hakbae Lee and Yangsoo Jang and Hwang, {Ki Chul}",
year = "2004",
month = "1",
day = "26",
doi = "10.1016/j.ejphar.2003.11.012",
language = "English",
volume = "484",
pages = "119--125",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",
number = "2-3",

}

Antiproliferative mechanisms of raxofelast (IRFI-016) in H 2 O 2 -stimulated rat aortic smooth muscle cells . / Lee, Kyung Hye; Lim, So Yeon; kang, seokmin; Kim, Dae Hyeok; Cho, Hong Keun; Chung, Ji Hyung; Kwon, Hyuck Moon; Chung, Kwang Hoe; Lee, Hakbae; Jang, Yangsoo; Hwang, Ki Chul.

In: European Journal of Pharmacology, Vol. 484, No. 2-3, 26.01.2004, p. 119-125.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Antiproliferative mechanisms of raxofelast (IRFI-016) in H 2 O 2 -stimulated rat aortic smooth muscle cells

AU - Lee, Kyung Hye

AU - Lim, So Yeon

AU - kang, seokmin

AU - Kim, Dae Hyeok

AU - Cho, Hong Keun

AU - Chung, Ji Hyung

AU - Kwon, Hyuck Moon

AU - Chung, Kwang Hoe

AU - Lee, Hakbae

AU - Jang, Yangsoo

AU - Hwang, Ki Chul

PY - 2004/1/26

Y1 - 2004/1/26

N2 - Reactive oxygen species-mediated cellular injury is involved in the pathogenesis of many diseases, including those affecting the cardiovascular system, such as myocardial ischemia-reperfusion injury, inflammation, and atheroscleosis. Raxofelast (IRFI-016; (±)-5-acetoxy-2, 3-dihydro-4, 6, 7-trimethyl-2-benzofuran-acetic acid) was designed with the aim of maximizing the antioxidant potency of phenols chemically related to vitamin E. The antioxidant activity of raxofelast has been convincingly demonstrated in several in vitro studies and in various models of ischemia-reperfusion injury. In this study, the antiproliferative effects of raxofelast were investigated to determine whether transduction signals and protooncogenes are affected in H 2 O 2 -stimulated rat aortic smooth muscle cells. In a tetrazolium-based colorimetric assay, the proliferation of rat aortic smooth muscle cells was increased by 3-fold in 0.1% fetal bovine serum/Dulbecco's modified Eagle's medium (DMEM) containing 500 μM H 2 O 2 , indicating that exogenous 500 μM H 2 O 2 was a growth stimulator of rat aortic smooth muscle cells. Exogenous H 2 O 2 significantly activated extracellular signal-regulated kinases (ERKs) activity within 30 min and raxofelast inhibited the ERKs activation dose dependently in 500 μM H 2 O 2 -stimulated rat aortic smooth muscle cells (IC 50 : 200 μM). Raxofelast reduced the intracellular reactive oxygen species generated by exogenous H 2 O 2 in a dose-dependent manner. In 500 μM H 2 O 2 -stimulated rat aortic smooth muscle cells, raxofelast dramatically attenuated the activation of mitogen-activating protein kinase (MAPK)/ERK kinase 1, 2 (MEK1,2) and protein kinase C (PKC) without affecting Ras expression. Induction of c-myc mRNA was significantly reduced dose dependently up to 100 μM by raxofelast in concentrations. These data indicate that the antiproliferative effects of raxofelast in H 2 O 2 - stimulated rat aortic smooth muscle cells may involve the suppression of intracellular reactive oxygen species formation and the inhibition of ERKs by inactivation through PKC and MEK1,2 and down-regulation of c-myc expression, regardless of Ras activation.

AB - Reactive oxygen species-mediated cellular injury is involved in the pathogenesis of many diseases, including those affecting the cardiovascular system, such as myocardial ischemia-reperfusion injury, inflammation, and atheroscleosis. Raxofelast (IRFI-016; (±)-5-acetoxy-2, 3-dihydro-4, 6, 7-trimethyl-2-benzofuran-acetic acid) was designed with the aim of maximizing the antioxidant potency of phenols chemically related to vitamin E. The antioxidant activity of raxofelast has been convincingly demonstrated in several in vitro studies and in various models of ischemia-reperfusion injury. In this study, the antiproliferative effects of raxofelast were investigated to determine whether transduction signals and protooncogenes are affected in H 2 O 2 -stimulated rat aortic smooth muscle cells. In a tetrazolium-based colorimetric assay, the proliferation of rat aortic smooth muscle cells was increased by 3-fold in 0.1% fetal bovine serum/Dulbecco's modified Eagle's medium (DMEM) containing 500 μM H 2 O 2 , indicating that exogenous 500 μM H 2 O 2 was a growth stimulator of rat aortic smooth muscle cells. Exogenous H 2 O 2 significantly activated extracellular signal-regulated kinases (ERKs) activity within 30 min and raxofelast inhibited the ERKs activation dose dependently in 500 μM H 2 O 2 -stimulated rat aortic smooth muscle cells (IC 50 : 200 μM). Raxofelast reduced the intracellular reactive oxygen species generated by exogenous H 2 O 2 in a dose-dependent manner. In 500 μM H 2 O 2 -stimulated rat aortic smooth muscle cells, raxofelast dramatically attenuated the activation of mitogen-activating protein kinase (MAPK)/ERK kinase 1, 2 (MEK1,2) and protein kinase C (PKC) without affecting Ras expression. Induction of c-myc mRNA was significantly reduced dose dependently up to 100 μM by raxofelast in concentrations. These data indicate that the antiproliferative effects of raxofelast in H 2 O 2 - stimulated rat aortic smooth muscle cells may involve the suppression of intracellular reactive oxygen species formation and the inhibition of ERKs by inactivation through PKC and MEK1,2 and down-regulation of c-myc expression, regardless of Ras activation.

UR - http://www.scopus.com/inward/record.url?scp=1642423773&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1642423773&partnerID=8YFLogxK

U2 - 10.1016/j.ejphar.2003.11.012

DO - 10.1016/j.ejphar.2003.11.012

M3 - Article

C2 - 14744595

AN - SCOPUS:1642423773

VL - 484

SP - 119

EP - 125

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 2-3

ER -