Published online before print February 3, 2005, doi: 10.1161/01.ATV.0000158311.24443.af
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© 2005 American Heart Association, Inc.
Atherosclerosis & Lipoproteins |
Physical Inactivity Increases Oxidative Stress, Endothelial Dysfunction, and Atherosclerosis
From the Klinik für Innere Medizin III (U.L., S.W., T.C., M.E., M.B., G.N.), Universitätsklinikum des Saarlandes, Homburg/Saar, and Med. Klinik und Poliklinik II (T.M.), Johannes Gutenberg-Universität, Mainz, Germany.
Correspondence to Dr Ulrich Laufs, Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, D-66421 Homburg/Saar, Germany. E-mail ulrich{at}laufs.com
Objective— Sedentary lifestyle is associated with increased cardiovascular events. The underlying molecular mechanisms are incompletely understood. Reactive oxygen species (ROS) contribute to endothelial dysfunction and atherosclerosis. An important source of vascular ROS is the NADPH oxidase.
Methods and Results— C57BL6 mice were subjected to regular housing (physical inactivity) or voluntary training on running wheels (6 weeks). Inactivity increased vascular lipid peroxidation to 148±9% and upregulated superoxide release to 176±17% (L-012 chemiluminescence) and 188±29% (cytochrome C reduction assay), respectively. ROS production was predominantly increased in the endothelium and the media (dihydroethidium fluorescence). Activity of the NADPH oxidase was increased to 154±22% in the sedentary group. Rac1 GST-PAK pull-down assays showed an upregulation of rac1 activity to 161±14%. Expression levels of the subunits nox1, p47phox, and p67phox were increased. To address the significance of the antioxidative effects of running, experiments were repeated in apolipoprotein E–deficient mice treated with a high-cholesterol diet. Inactivity increased vascular superoxide production and impaired endothelium-dependent vasorelaxation. Atherosclerotic lesion formation was significantly accelerated in sedentary mice.
Conclusions— Inactivity increases vascular NADPH oxidase expression and activity and enhances vascular ROS production, which contributes to endothelial dysfunction and atherosclerosis during sedentary as opposed to physically active lifestyle.
Sedentary lifestyle predicts vascular risk. To study underlying mechanisms, mice were subjected to physical inactivity or voluntary training on running wheels. Inactivity increased vascular lipid peroxidation, superoxide release, and NADPH oxidase expression and activity. In apoE–/– mice, inactivity significantly impaired endothelium-dependent vasorelaxation and accelerated atherosclerotic lesion formation.
Key Words: physical inactivity • exercise • oxidative stress • endothelial dysfunction • atherosclerosis
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