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Atherosclerosis is a focal disease affecting medium to large size arteries in the human body. In these vessels, fibrous plaques are preferentially located at branches and bifurcations. The localization of atherosclerotic plaques seems to correlate with areas of reduced laminar shear stress with cyclic stretch being enhanced. In this study we screened for potential mechanosensors and effector kinases involved in deformation-induced gene expression in cultured human endothelial cells (HUVEC) using appropriate pharmacological inhibitors. As a readout for shear stress and cyclic stretch dependent gene expression, both mRNA and protein levels of nitric oxide synthase (NOS-3) and glutathione peroxidase (GSH-Px) were monitored. First results demonstrate an activation of c-Jun N-terminal kinase followed by nuclear translocation of the transcription factor AP-1 (activator protein-1) in response to both shear stress and cyclic stretch. In contrast, the p38 MAP kinase pathway with consecutive activation of C/EBP (CCAAT enhancer binding protein) was stimulated by cyclic stretch only. Moreover, shear stress-induced NOS-3 expression was attenuated by cyclodextrin-mediated cholesterol depletion (i.e. destruction of caveolae) but not by blockade of mechanosensitive cation channels. Moreover, down-regulation of GSH-Px protein expression by antisense oligonucleotides resulted in an increased capacity of the cells to generate reactive oxygen species, namely hydrogen peroxide, and augmented the stretch-induced pro-atherosclerotic expression of monocyte chemoattractant protein-1, vascular cell adhesion molecule-1 and CD40. These results potentially provide an insight into the molecular mechanisms involved in the early phase of atherogenesis.
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J. Vasc. Biol. 42, Sup:2 (2005) pp59-60