Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3588-3592
© 1997 American Heart Association, Inc.
Articles |
Shear Stress Inhibits H2O2-Induced Apoptosis of Human Endothelial Cells by Modulation of the Glutathione Redox Cycle and Nitric Oxide Synthase
From the Molecular Cardiology Group, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany.
Correspondence to Stefanie Dimmeler, Department of Internal Medicine IV, Division of Cardiology, University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Dimmeler{at}em.uni-frankfurt.de
Abstract Physiological levels of shear
stress reduce endothelial cell turnover and exert a
potent antiatherosclerotic effect. Here we demonstrate that oxidative
stress-induced apoptosis of human endothelial
cells was inhibited by shear stress exposure (15
dynes/cm2). Incubation with H2O2
(200 µmol/L) for 18 hours induced apoptosis of human
umbilical venous endothelial cells as demonstrated by
an enzyme-linked immunosorbent assay specific for histone-associated
DNA fragments and visual analysis of
fluorescence-stained nuclei. Shear stress-mediated inhibition
of apoptosis was partially prevented by pharmacological
inhibition of glutathione (GSH) biosynthesis with buthionine
sulfoximine (BSO) or nitric oxide (NO) synthase with
NG-monomethyl-L-arginine
(LNMA), whereas inhibition of catalase by aminotriazol did not affect
the inhibitory action of shear stress. Combined inhibition
of NO synthase and GSH biosynthesis completely reversed the protective
effect of shear stress, suggesting that both NO synthase and the GSH
redox cycle system are involved in the apoptosis-suppressing
effect of shear stress. Similar results were obtained when
apoptosis was stimulated by tumor necrosis factor 
(TNF).
To gain further insights into the interference of shear stress with
apoptosis signal transduction, we measured caspase-3-like
activity, a cysteine protease that has been shown to play a predominant
role in the cell death effector pathway. Indeed, shear stress prevented
the activation of caspase-3-like activity induced by
H2O2 or TNF. The inhibitory
effect of shear stress was prevented by LNMA and BSO, suggesting that
the reduction of oxidative flux by shear stress prevents the activation
of caspase-like proteases and thereby inhibits apoptotic cell
death in human endothelial cells.
Key Words: DNA • atherosclerosis • oxygen radicals • antioxidants
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