Upregulation of glutathione peroxidase offsets stretch-induced proatherogenic gene expression in human endothelial cells.
OBJECTIVE
Localization of atherosclerotic plaques typically correlates with areas of biomechanical strain where shear stress is decreased while stretch, thought to promote atherogenesis through enhanced oxidative stress, is increased.


RESULTS
In human cultured endothelial cells, nitric oxide synthase expression was exclusively shear stress-dependent whereas expression of glutathione peroxidase-1 (GPx-1), but not that of Cu(2+)/Zn(2+)-superoxide dismutase or Mn(2+)-superoxide dismutase, was upregulated solely in response to cyclic stretch. GPx-1 expression was also enhanced in isolated mouse arteries perfused at high pressure. Combined pharmacological and decoy oligodeoxynucleotide blockade revealed that activation of p38 MAP kinase followed by nuclear translocation of CCAAT/enhancer binding protein plays a pivotal role in stretch-induced GPx-1 expression in human endothelial cells. Antisense oligodeoxynucleotide knockdown of GPx-1 reinforced both their capacity to generate hydrogen peroxide and the transient stretch-induced expression of CD40, monocyte chemoatractant protein-1, and vascular cell adhesion molecule-1. Consequently, THP-1 monocyte adhesion to the GPx-1-depleted cells was augmented.


CONCLUSIONS
Stretch-induced proatherosclerotic gene expression in human endothelial cells seems to be hydrogen peroxide-mediated. The concomitant rise in GPx-1 expression, but not that of other antioxidant enzymes, may comprise an adaptive mechanism through which the cells maintain their antiatherosclerotic properties in spite of a decreased bioavailability of nitric oxide.
Wagner
Andreas H
AH
Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, University Hospital Heidelberg, Heidelberg, Germany.
Kautz
Ocko
O
Fricke
Kathrin
K
Zerr-Fouineau
Murielle
M
Demicheva
Elena
E
Güldenzoph
Björn
B
Bermejo
Justo Lorenzo
JL
Korff
Thomas
T
Hecker
Markus
M
D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology*; D004789:Enzyme Activation / Q000235:genetics; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013314:Stress, Mechanical; D015854:Up-Regulation
D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; D019001:Nitric Oxide Synthase