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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1894.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Upregulation of Glutathione Peroxidase Offsets Stretch-Induced Proatherogenic Gene Expression in Human Endothelial Cells

Andreas H. Wagner; Ocko Kautz; Kathrin Fricke; Murielle Zerr-Fouineau; Elena Demicheva; Björn Güldenzoph; Justo Lorenzo Bermejo; Thomas Korff; Markus Hecker

From the Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology (A.H.W., O.K., K.F., M.Z.-F., E.D., B.G., T.K., M.H.), and the Institute of Medical Biometry and Informatics (J.L.B.), University Hospital Heidelberg, Germany.

Correspondence to Dr Markus Hecker, Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, University of Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany. E-mail hecker{at}physiologie.uni-hd.de

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.

Methods and 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 Cu²⁺/Zn²⁺-superoxide dismutase or Mn²⁺-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.

Upregulation of glutathione peroxidase-1 in human endothelial cells prevents hydrogen peroxide–mediated proatherosclerotic gene expression in response to cyclic stretch. In comparison with the dismutation of superoxide anions, accelerating the degradation of hydrogen peroxide may constitute an at least equally important adaptive mechanism to maintain the antiatherosclerotic properties of these cells.

Key Words: glutathione peroxidase • oxidative stress • cyclic stretch • endothelial cells • atherosclerosis