Published online before print September 19, 2002, doi: 10.1161/01.RES.0000037981.97541.25
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Submitted on March 1, 2002
Revised on August 20, 2002
Accepted on September 4, 2002
Fluid Shear Stress Attenuates Hydrogen Peroxide-Induced c-Jun-NH2-Terminal Kinase Activation via a Glutathione Reductase-Mediated Mechanism
Yukihiro Hojo ;
From the Center for Cardiovascular Research (Y.H., Y.S., T.T., R.J.H., C.P.B., K.Y., J.H., B.C.B.), Cardiology Unit, Department of Medicine, University of Rochester, Rochester, NY; and the Departments of Medicine and Physiology (R.A.), University of Kentucky, Lexington, Ky.
* To whom correspondence should be addressed. E-mail: bradford_berk{at}urmc.rochester.edu.
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 µmol/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 dynes/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)-1-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.
Key words: oxidative stress • endothelial cell • signal transduction
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