Activation of p38 MAPK by oxidative stress underlying epirubicin-induced vascular endothelial cell injury

Takaaki Yamada, Nobuaki Egashira, Ayami Bando, Yui Nishime, Yuki Tonogai, Maiko Imuta, Takahisa Yano, Ryozo Oishi

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Epirubicin, an anthracycline antitumor drug, often causes vascular injury such as vascular pain, phlebitis, and necrotizing vasculitis. However, an effective prevention for the epirubicin-induced vascular injury has not been established. The purpose of this study is to identify the mechanisms of cell injury induced by epirubicin in porcine aorta endothelial cells (PAECs). PAECs were exposed to epirubicin for 10 min followed by further incubation without epirubicin. The exposure to epirubicin (3-30 μM) decreased the cell viability concentration and time dependently. Epirubicin increased the activity of caspase-3/7, apoptotic cells, and intracellular lipid peroxide levels, and also induced depolarization of mitochondrial membranes. These intracellular events were reversed by glutathione (GSH) and N-acetylcysteine (NAC), while epirubicin rather increased intracellular GSH slightly and l-buthionine-(S,R)-sulfoximine, a specific inhibitor of GSH synthesis, had no effect on the epirubicin-induced cell injury. The epirubicin-induced cell injury and increase of caspase-3/7 activity were also attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors, SB203580 and PD169316. Moreover, epirubicin significantly enhanced the phosphorylation of p38 MAPK, and these effects were attenuated by GSH and NAC. In contrast, a c-Jun N-terminal kinase inhibitor SP600125, an extracellular signal-regulated kinase inhibitor PD98059, and a p53 inhibitor pifithrin α did not affect the epirubicin-induced cell injury and increase of caspase-3/7 activity. These results indicate that an activation of p38 MAPK by oxidative stress is involved in the epirubicin-induced endothelial cell injury.

Original languageEnglish
Pages (from-to)1285-1293
Number of pages9
JournalFree Radical Biology and Medicine
Volume52
Issue number8
DOIs
Publication statusPublished - Apr 15 2012

Fingerprint

Epirubicin
Oxidative stress
Endothelial cells
p38 Mitogen-Activated Protein Kinases
Oxidative Stress
Endothelial Cells
Chemical activation
Wounds and Injuries
Caspase 7
Caspase 3
Vascular System Injuries
Acetylcysteine
Aorta
Swine
Cells
Phlebitis
Phosphorylation
JNK Mitogen-Activated Protein Kinases
Lipid Peroxides
Anthracyclines

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Cite this

Activation of p38 MAPK by oxidative stress underlying epirubicin-induced vascular endothelial cell injury. / Yamada, Takaaki; Egashira, Nobuaki; Bando, Ayami; Nishime, Yui; Tonogai, Yuki; Imuta, Maiko; Yano, Takahisa; Oishi, Ryozo.

In: Free Radical Biology and Medicine, Vol. 52, No. 8, 15.04.2012, p. 1285-1293.

Research output: Contribution to journalArticle

Yamada, Takaaki ; Egashira, Nobuaki ; Bando, Ayami ; Nishime, Yui ; Tonogai, Yuki ; Imuta, Maiko ; Yano, Takahisa ; Oishi, Ryozo. / Activation of p38 MAPK by oxidative stress underlying epirubicin-induced vascular endothelial cell injury. In: Free Radical Biology and Medicine. 2012 ; Vol. 52, No. 8. pp. 1285-1293.
@article{fe6bf2d23bcd49e3b7f9003d818bb56d,
title = "Activation of p38 MAPK by oxidative stress underlying epirubicin-induced vascular endothelial cell injury",
abstract = "Epirubicin, an anthracycline antitumor drug, often causes vascular injury such as vascular pain, phlebitis, and necrotizing vasculitis. However, an effective prevention for the epirubicin-induced vascular injury has not been established. The purpose of this study is to identify the mechanisms of cell injury induced by epirubicin in porcine aorta endothelial cells (PAECs). PAECs were exposed to epirubicin for 10 min followed by further incubation without epirubicin. The exposure to epirubicin (3-30 μM) decreased the cell viability concentration and time dependently. Epirubicin increased the activity of caspase-3/7, apoptotic cells, and intracellular lipid peroxide levels, and also induced depolarization of mitochondrial membranes. These intracellular events were reversed by glutathione (GSH) and N-acetylcysteine (NAC), while epirubicin rather increased intracellular GSH slightly and l-buthionine-(S,R)-sulfoximine, a specific inhibitor of GSH synthesis, had no effect on the epirubicin-induced cell injury. The epirubicin-induced cell injury and increase of caspase-3/7 activity were also attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors, SB203580 and PD169316. Moreover, epirubicin significantly enhanced the phosphorylation of p38 MAPK, and these effects were attenuated by GSH and NAC. In contrast, a c-Jun N-terminal kinase inhibitor SP600125, an extracellular signal-regulated kinase inhibitor PD98059, and a p53 inhibitor pifithrin α did not affect the epirubicin-induced cell injury and increase of caspase-3/7 activity. These results indicate that an activation of p38 MAPK by oxidative stress is involved in the epirubicin-induced endothelial cell injury.",
author = "Takaaki Yamada and Nobuaki Egashira and Ayami Bando and Yui Nishime and Yuki Tonogai and Maiko Imuta and Takahisa Yano and Ryozo Oishi",
year = "2012",
month = "4",
day = "15",
doi = "10.1016/j.freeradbiomed.2012.02.003",
language = "English",
volume = "52",
pages = "1285--1293",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "8",

}

TY - JOUR

T1 - Activation of p38 MAPK by oxidative stress underlying epirubicin-induced vascular endothelial cell injury

AU - Yamada, Takaaki

AU - Egashira, Nobuaki

AU - Bando, Ayami

AU - Nishime, Yui

AU - Tonogai, Yuki

AU - Imuta, Maiko

AU - Yano, Takahisa

AU - Oishi, Ryozo

PY - 2012/4/15

Y1 - 2012/4/15

N2 - Epirubicin, an anthracycline antitumor drug, often causes vascular injury such as vascular pain, phlebitis, and necrotizing vasculitis. However, an effective prevention for the epirubicin-induced vascular injury has not been established. The purpose of this study is to identify the mechanisms of cell injury induced by epirubicin in porcine aorta endothelial cells (PAECs). PAECs were exposed to epirubicin for 10 min followed by further incubation without epirubicin. The exposure to epirubicin (3-30 μM) decreased the cell viability concentration and time dependently. Epirubicin increased the activity of caspase-3/7, apoptotic cells, and intracellular lipid peroxide levels, and also induced depolarization of mitochondrial membranes. These intracellular events were reversed by glutathione (GSH) and N-acetylcysteine (NAC), while epirubicin rather increased intracellular GSH slightly and l-buthionine-(S,R)-sulfoximine, a specific inhibitor of GSH synthesis, had no effect on the epirubicin-induced cell injury. The epirubicin-induced cell injury and increase of caspase-3/7 activity were also attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors, SB203580 and PD169316. Moreover, epirubicin significantly enhanced the phosphorylation of p38 MAPK, and these effects were attenuated by GSH and NAC. In contrast, a c-Jun N-terminal kinase inhibitor SP600125, an extracellular signal-regulated kinase inhibitor PD98059, and a p53 inhibitor pifithrin α did not affect the epirubicin-induced cell injury and increase of caspase-3/7 activity. These results indicate that an activation of p38 MAPK by oxidative stress is involved in the epirubicin-induced endothelial cell injury.

AB - Epirubicin, an anthracycline antitumor drug, often causes vascular injury such as vascular pain, phlebitis, and necrotizing vasculitis. However, an effective prevention for the epirubicin-induced vascular injury has not been established. The purpose of this study is to identify the mechanisms of cell injury induced by epirubicin in porcine aorta endothelial cells (PAECs). PAECs were exposed to epirubicin for 10 min followed by further incubation without epirubicin. The exposure to epirubicin (3-30 μM) decreased the cell viability concentration and time dependently. Epirubicin increased the activity of caspase-3/7, apoptotic cells, and intracellular lipid peroxide levels, and also induced depolarization of mitochondrial membranes. These intracellular events were reversed by glutathione (GSH) and N-acetylcysteine (NAC), while epirubicin rather increased intracellular GSH slightly and l-buthionine-(S,R)-sulfoximine, a specific inhibitor of GSH synthesis, had no effect on the epirubicin-induced cell injury. The epirubicin-induced cell injury and increase of caspase-3/7 activity were also attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors, SB203580 and PD169316. Moreover, epirubicin significantly enhanced the phosphorylation of p38 MAPK, and these effects were attenuated by GSH and NAC. In contrast, a c-Jun N-terminal kinase inhibitor SP600125, an extracellular signal-regulated kinase inhibitor PD98059, and a p53 inhibitor pifithrin α did not affect the epirubicin-induced cell injury and increase of caspase-3/7 activity. These results indicate that an activation of p38 MAPK by oxidative stress is involved in the epirubicin-induced endothelial cell injury.

UR - http://www.scopus.com/inward/record.url?scp=84857991374&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857991374&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2012.02.003

DO - 10.1016/j.freeradbiomed.2012.02.003

M3 - Article

VL - 52

SP - 1285

EP - 1293

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - 8

ER -