Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis

Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):809-14. doi: 10.1161/ Epub 2005 Feb 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / genetics
  • Arteriosclerosis / metabolism*
  • Arteriosclerosis / pathology
  • Arteriosclerosis / physiopathology
  • Endothelium, Vascular / enzymology*
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology
  • Life Style
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • NADH, NADPH Oxidoreductases / metabolism
  • NADPH Oxidase 1
  • NADPH Oxidases
  • Neuropeptides / metabolism
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Oxidative Stress / physiology*
  • Phosphoproteins / metabolism
  • Physical Conditioning, Animal*
  • RNA, Messenger / analysis
  • Reactive Oxygen Species / metabolism
  • Vasodilation / physiology
  • rac GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein


  • Apolipoproteins E
  • Neuropeptides
  • Phosphoproteins
  • RNA, Messenger
  • Rac1 protein, mouse
  • Reactive Oxygen Species
  • neutrophil cytosol factor 67K
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • NADH, NADPH Oxidoreductases
  • NADPH Oxidase 1
  • NADPH Oxidases
  • NOX1 protein, mouse
  • neutrophil cytosolic factor 1
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein