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Am J Physiol Heart Circ Physiol (February 21, 2003). doi:10.1152/ajpheart.00360.2001
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Submitted on April 30, 2001
Accepted on February 5, 2003

NOS Inhibition Accelerates Atherogenesis: Reversal by Exercise

Josef Niebauer1, Andrew J. Maxwell2, Patrick S. Lin2, David Wang2, Philip S. Tsao2, and John P. Cooke2*

1 Section of Vascular Medicine, Divisions of Cardiovascular Medicine, Stanford University, Stanford, CA, USA; Department of Cardiology, University of Leipzig - Heart Center, Leipzig, Germany
2 Section of Vascular Medicine, Divisions of Cardiovascular Medicine, Stanford University, Stanford, CA, USA

* To whom correspondence should be addressed. E-mail: john.cooke{at}stanford.edu.

Background In this study we assessed the effects of chronic exercise training (12 weeks) on atherosclerotic lesion formation in hypercholesterolemic apolipoprotein-E deficient mice (n=31). Methods and Results At the age of 9 weeks mice were assigned to the following groups: sedentary (Sed; n=9); exercise (Ex; n=12); sedentary and oral L-nitroarginine (Sed-NA; n=4), or exercise and oral L-nitroarginine (Ex-NA; n=6). Chronic exercise training was performed on a treadmill for 12 weeks, 6x/week, 2x1hr/d, at a final speed of 22m/min, and an 8° grade. LNA was discontinued 5 days prior to final treadmill testing. The farthest distance run to exhaustion was observed in Ex-NA mice (Sed: 306 ± 32 m; Ex: 640±87; Sed-NA: 451 ± 109 m; Ex-NA: 820 ± 49 m; all p<0.05). Lesion formation was assessed in the proximal ascending aorta by dissection microscopy after oil red O staining. The aortae of Sed-NA mice manifested a threefold increase in lesion formation as compared to the other groups. This LNA-induced lesion formation was reduced by chronic exercise training (Sed: 786 ± 144; Ex: 780 ± 206; Sed-NA: 2147 ± 522; Ex-NA: 851 ± 253; Sed-NA vs. all other groups: p<0.001). Conclusion Treatment with oral LNA (an NO synthase antagonist) leads to accelerated atherogenesis in genetically determined hypercholesterolemic mice. This adverse effect can be overcome by chronic exercise training.




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