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

Center for Cardiovascular Research, Cardiology Unit, Department of Medicine, University of Rochester, Rochester, NY 14642, USA.
Circulation Research (Impact Factor: 11.02). 11/2002; 91(8):712-8.
Source: PubMed


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 micro mol/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)-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.

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    • "However, unlike the effect of these kinase inhibitors on HO-1 induction, we observed that only inhibition of the JNK pathway appeared to modulate the adaptive increases in reduced GSH levels. This is similar to findings in bovine endothelial cells implicating a role for the JNK pathway in modulating intracellular GSH homeostasis by hydrogen peroxide [35]. Our study has shown for the first time that inhibition of MAPK signaling pathways can attenuate induction of HO-1 in response to well-defined species of oxidized LDL. "
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    • "JNK is activated by a number of cellular stimuli including proinflammatory cytokines and ROS. Hojo et al. [31] demonstrated JNK activation by ROS in endothelial cells via the modulation of cellular protection systems against ROS. It is speculated that JNK plays an important role in signal events through the phosphorylation of c-Jun, activation of AP-1, and stimulation of proinflammatory gene expression such as ICAM-1. "
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    ABSTRACT: Two Rokumi-jio-gan-containing prescriptions (Hachimi-jio-gan and Bakumi-jio-gan) were selected to examine their actions in nephrectomized rats. Each prescription was given orally to rats for 10 weeks after the excision of five-sixths of their kidney volumes, and its effect was compared with non-nephrectomized and normal rats. Rats given Hachimi-jio-gan and Bakumi-jio-gan showed an improvement of renal functional parameters such as serum urea nitrogen, creatinine, creatinine clearance, and urinary protein. The nephrectomized rats exhibited the up-regulation of nicotinamide adenine dinucleotide phosphate oxidase subunits, c-Jun N-terminal kinase (JNK), phosphor-JNK, c-Jun, transforming growth factor-β(1), nuclear factor-kappa B, cyclooxygenase-2, inducible nitric oxide synthase, monocyte chemotactic protein-1, intracellular adhesion molecule-1, Bax, cytochrome c, and caspase-3, and down-regulation of NF-E2-related factor 2, heme oxygenase-1, and survivin; however, Bakumi-jio-gan administration acts as a regulator in inflammatory reactions caused by oxidative stress in renal failure. Moreover, the JNK pathway and apoptosis-related protein expressions, Bax, caspase-3, and survivin, were ameliorated to the normal levels by Hachimi-jio-gan administration. The development of renal lesions, glomerular sclerosis, tubulointerstitial damage, and arteriolar sclerotic lesions, estimated by histopathological evaluation and scoring, was strong in the groups administered Hachimi-jio-gan rather than Bakumi-jio-gan. This study suggests that Rokumi-jio-gan-containing prescriptions play a protective role in the progression of renal failure.
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    • "This uncoupling converts eNOS into an accelerator of redox signaling followed by the production of large amounts of ROS inducing a proinflammatory state (Rabelink & Luscher, 2006). Several enzymes such as the hemoxygenase system (Ryter et al., 2006), antioxidant enzymes, thioredoxin reductase and glutathione reductase (Hojo et al., 2002) can scavenge ROS and " fine-tune " this activation cascade, to the extent that ROS exceed the antioxidative capacity of cellular antioxidants (Cai & Harrison, 2000). This process explains how the chronic activation of the endothelium or impaired activity of eNOS can lead to the endothelial dysfunction. "
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