Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis.
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.


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.
Laufs
Ulrich
U
Klinik für Innere Medizin III, niversitätsklinikum des Saarlandes, Homburg/Saar, Germany. ulrich@laufs.com
Wassmann
Sven
S
Czech
Thomas
T
Münzel
Thomas
T
Eisenhauer
Marco
M
Böhm
Michael
M
Nickenig
Georg
G
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008019:Life Style; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; D009479:Neuropeptides / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D010805:Physical Conditioning, Animal; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
D001057:Apolipoproteins E; D009479:Neuropeptides; D010750:Phosphoproteins; D012333:RNA, Messenger; C484602:Rac1 protein, mouse; D017382:Reactive Oxygen Species; C079789:neutrophil cytosol factor 67K; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C060505:neutrophil cytosolic factor 1; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein