Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathione reductase-mediated mechanism

Yukihiro Hojo, Yuji Saito, Tatsuo Tanimoto, Ryan J. Hoefen, Christopher P. Baines, Kei Yamamoto, Judith Haendeler, Reto Asmis, Bradford C. Berk

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

c-Jun NH2-terminal kinase (JNK) is activated by a number of cellular stimuli including reactive oxygen species (ROS). Previous studies have demonstrated that fluid shear stress (flow) inhibits cytokine-induced JNK activation in endothelial cells (ECs). In the present study, we show JNK activation by ROS in ECs and hypothesized that flow inhibits ROS-induced JNK activation in ECs via modulation of cellular protection systems against ROS. JNK was activated by 300 μmo1/L hydrogen peroxide (H2O2) in bovine lung microvascular ECs (BLMVECs) with a peak at 60 minutes after stimulation (6.3±1.2-fold increase). Preexposure of BLMVECs to physiological steady laminar flow (shear stress= 12 dyne/cm2) for 10 minutes significantly decreased H2O2-induced JNK activation. Thioredoxin and glutathione are cellular antioxidants that protect cells against ROS. Flow induced a significant increase in the ratio of reduced glutathione to oxidized glutathione consistent with a 1.6-fold increase in glutathione reductase (GR) activity. Preincubation of BLMVECs with the GR inhibitor, 1,3 bis-(2 chloroethyl)-l-nitrosourea, abolished the inhibitory effect of flow. In contrast, preincubation of BLMVECs with azelaic acid, a specific inhibitor for thioredoxin reductase, did not alter the effect of flow on H2O2-induced JNK activation. Overexpression of GR mimicked the effect of flow to inhibit JNK activation. These results suggest that flow activates GR, an important regulator of the intracellular redox state of glutathione, and exerts a protective mechanism against oxidative stress in endothelial cells.

Original languageEnglish (US)
Pages (from-to)712-718
Number of pages7
JournalCirculation Research
Volume91
Issue number8
DOIs
StatePublished - Oct 18 2002
Externally publishedYes

Fingerprint

Glutathione Reductase
JNK Mitogen-Activated Protein Kinases
Hydrogen Peroxide
Reactive Oxygen Species
Endothelial Cells
Glutathione
Lung
Thioredoxin-Disulfide Reductase
Thioredoxins
Glutathione Disulfide
Oxidation-Reduction
Oxidative Stress
Antioxidants
Cytokines

Keywords

  • Endothelial cell
  • Oxidative stress
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathione reductase-mediated mechanism. / Hojo, Yukihiro; Saito, Yuji; Tanimoto, Tatsuo; Hoefen, Ryan J.; Baines, Christopher P.; Yamamoto, Kei; Haendeler, Judith; Asmis, Reto; Berk, Bradford C.

In: Circulation Research, Vol. 91, No. 8, 18.10.2002, p. 712-718.

Research output: Contribution to journalArticle

Hojo, Y, Saito, Y, Tanimoto, T, Hoefen, RJ, Baines, CP, Yamamoto, K, Haendeler, J, Asmis, R & Berk, BC 2002, 'Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathione reductase-mediated mechanism', Circulation Research, vol. 91, no. 8, pp. 712-718. https://doi.org/10.1161/01.RES.0000037981.97541.25
Hojo, Yukihiro ; Saito, Yuji ; Tanimoto, Tatsuo ; Hoefen, Ryan J. ; Baines, Christopher P. ; Yamamoto, Kei ; Haendeler, Judith ; Asmis, Reto ; Berk, Bradford C. / Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathione reductase-mediated mechanism. In: Circulation Research. 2002 ; Vol. 91, No. 8. pp. 712-718.
@article{46007916f4bb4b23a734e528dd7b7ee7,
title = "Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathione reductase-mediated mechanism",
abstract = "c-Jun NH2-terminal kinase (JNK) is activated by a number of cellular stimuli including reactive oxygen species (ROS). Previous studies have demonstrated that fluid shear stress (flow) inhibits cytokine-induced JNK activation in endothelial cells (ECs). In the present study, we show JNK activation by ROS in ECs and hypothesized that flow inhibits ROS-induced JNK activation in ECs via modulation of cellular protection systems against ROS. JNK was activated by 300 μmo1/L hydrogen peroxide (H2O2) in bovine lung microvascular ECs (BLMVECs) with a peak at 60 minutes after stimulation (6.3±1.2-fold increase). Preexposure of BLMVECs to physiological steady laminar flow (shear stress= 12 dyne/cm2) for 10 minutes significantly decreased H2O2-induced JNK activation. Thioredoxin and glutathione are cellular antioxidants that protect cells against ROS. Flow induced a significant increase in the ratio of reduced glutathione to oxidized glutathione consistent with a 1.6-fold increase in glutathione reductase (GR) activity. Preincubation of BLMVECs with the GR inhibitor, 1,3 bis-(2 chloroethyl)-l-nitrosourea, abolished the inhibitory effect of flow. In contrast, preincubation of BLMVECs with azelaic acid, a specific inhibitor for thioredoxin reductase, did not alter the effect of flow on H2O2-induced JNK activation. Overexpression of GR mimicked the effect of flow to inhibit JNK activation. These results suggest that flow activates GR, an important regulator of the intracellular redox state of glutathione, and exerts a protective mechanism against oxidative stress in endothelial cells.",
keywords = "Endothelial cell, Oxidative stress, Signal transduction",
author = "Yukihiro Hojo and Yuji Saito and Tatsuo Tanimoto and Hoefen, {Ryan J.} and Baines, {Christopher P.} and Kei Yamamoto and Judith Haendeler and Reto Asmis and Berk, {Bradford C.}",
year = "2002",
month = "10",
day = "18",
doi = "10.1161/01.RES.0000037981.97541.25",
language = "English (US)",
volume = "91",
pages = "712--718",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

TY - JOUR

T1 - Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathione reductase-mediated mechanism

AU - Hojo, Yukihiro

AU - Saito, Yuji

AU - Tanimoto, Tatsuo

AU - Hoefen, Ryan J.

AU - Baines, Christopher P.

AU - Yamamoto, Kei

AU - Haendeler, Judith

AU - Asmis, Reto

AU - Berk, Bradford C.

PY - 2002/10/18

Y1 - 2002/10/18

N2 - c-Jun NH2-terminal kinase (JNK) is activated by a number of cellular stimuli including reactive oxygen species (ROS). Previous studies have demonstrated that fluid shear stress (flow) inhibits cytokine-induced JNK activation in endothelial cells (ECs). In the present study, we show JNK activation by ROS in ECs and hypothesized that flow inhibits ROS-induced JNK activation in ECs via modulation of cellular protection systems against ROS. JNK was activated by 300 μmo1/L hydrogen peroxide (H2O2) in bovine lung microvascular ECs (BLMVECs) with a peak at 60 minutes after stimulation (6.3±1.2-fold increase). Preexposure of BLMVECs to physiological steady laminar flow (shear stress= 12 dyne/cm2) for 10 minutes significantly decreased H2O2-induced JNK activation. Thioredoxin and glutathione are cellular antioxidants that protect cells against ROS. Flow induced a significant increase in the ratio of reduced glutathione to oxidized glutathione consistent with a 1.6-fold increase in glutathione reductase (GR) activity. Preincubation of BLMVECs with the GR inhibitor, 1,3 bis-(2 chloroethyl)-l-nitrosourea, abolished the inhibitory effect of flow. In contrast, preincubation of BLMVECs with azelaic acid, a specific inhibitor for thioredoxin reductase, did not alter the effect of flow on H2O2-induced JNK activation. Overexpression of GR mimicked the effect of flow to inhibit JNK activation. These results suggest that flow activates GR, an important regulator of the intracellular redox state of glutathione, and exerts a protective mechanism against oxidative stress in endothelial cells.

AB - c-Jun NH2-terminal kinase (JNK) is activated by a number of cellular stimuli including reactive oxygen species (ROS). Previous studies have demonstrated that fluid shear stress (flow) inhibits cytokine-induced JNK activation in endothelial cells (ECs). In the present study, we show JNK activation by ROS in ECs and hypothesized that flow inhibits ROS-induced JNK activation in ECs via modulation of cellular protection systems against ROS. JNK was activated by 300 μmo1/L hydrogen peroxide (H2O2) in bovine lung microvascular ECs (BLMVECs) with a peak at 60 minutes after stimulation (6.3±1.2-fold increase). Preexposure of BLMVECs to physiological steady laminar flow (shear stress= 12 dyne/cm2) for 10 minutes significantly decreased H2O2-induced JNK activation. Thioredoxin and glutathione are cellular antioxidants that protect cells against ROS. Flow induced a significant increase in the ratio of reduced glutathione to oxidized glutathione consistent with a 1.6-fold increase in glutathione reductase (GR) activity. Preincubation of BLMVECs with the GR inhibitor, 1,3 bis-(2 chloroethyl)-l-nitrosourea, abolished the inhibitory effect of flow. In contrast, preincubation of BLMVECs with azelaic acid, a specific inhibitor for thioredoxin reductase, did not alter the effect of flow on H2O2-induced JNK activation. Overexpression of GR mimicked the effect of flow to inhibit JNK activation. These results suggest that flow activates GR, an important regulator of the intracellular redox state of glutathione, and exerts a protective mechanism against oxidative stress in endothelial cells.

KW - Endothelial cell

KW - Oxidative stress

KW - Signal transduction

UR - http://www.scopus.com/inward/record.url?scp=0037131208&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037131208&partnerID=8YFLogxK

U2 - 10.1161/01.RES.0000037981.97541.25

DO - 10.1161/01.RES.0000037981.97541.25

M3 - Article

C2 - 12386148

AN - SCOPUS:0037131208

VL - 91

SP - 712

EP - 718

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 8

ER -