Long-term combined beneficial effects of physical training and metabolic treatment on atherosclerosis in hypercholesterolemic mice

Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8797-802. doi: 10.1073/pnas.0402734101. Epub 2004 May 28.


The pathogenic mechanisms by which physical exercise influences atherosclerotic lesion formation remain poorly understood. Because vigorous physical training increases oxidative stress, this study tested the hypothesis that graduated and moderate physical exercise together with metabolic intervention (l-arginine and antioxidants) may contribute to increased vascular protection. Exercise training in mice was induced by graduated swimming. In hypercholesterolemic male mice on an atherogenic high-cholesterol diet, graduated and moderate exercise lowered plasma cholesterol and decreased atherosclerotic lesions compared with sedentary control mice. Antioxidants (1.0% vitamin E added to the chow and 0.05% vitamin C added to the drinking water) and l-arginine (6% in drinking water) supplementation to exercising hypercholesterolemic mice further and synergistically reduced atherosclerosis compared with untreated exercised mice. Arterial oxidation-specific epitopes and systemic oxidative stress were reduced by metabolic intervention. Graduated chronic exercise elicited an increase in production of nitric oxide through increased endothelial nitric oxide synthase expression and ameliorated scavenger activities. Thus, metabolic intervention with l-arginine and antioxidants together with graduated and moderate exercise training reduce atherosclerotic lesion formation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antioxidants / therapeutic use*
  • Arginine / therapeutic use
  • Arteriosclerosis / etiology
  • Arteriosclerosis / metabolism
  • Arteriosclerosis / prevention & control*
  • Ascorbic Acid / therapeutic use
  • Diet, Atherogenic
  • Hyperlipoproteinemia Type II / complications*
  • Hyperlipoproteinemia Type II / metabolism
  • Hyperlipoproteinemia Type II / therapy*
  • Male
  • Mice
  • Mice, Knockout
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Oxidative Stress
  • Physical Conditioning, Animal*
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Vitamin E / therapeutic use


  • Antioxidants
  • Receptors, LDL
  • Vitamin E
  • Arginine
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos2 protein, mouse
  • Nos3 protein, mouse
  • Ascorbic Acid