NOS inhibition accelerates atherogenesis: reversal by exercise.
In this study, we assessed the effects of chronic exercise training (12 wk) on atherosclerotic lesion formation in hypercholesterolemic apolipoprotein E-deficient mice (n = 31). At the age of 9 wk, mice were assigned to the following groups: sedentary (Sed; n = 9); exercise (Ex; n = 12); sedentary and oral NG-nitro-L-arginine (L-NNA, Sed-NA; n = 4), or exercise and oral L-NNA (Ex-NA; n = 6). Chronic exercise training was performed on a treadmill for 12 wk (6 times/wk and twice for 1 h/day) at a final speed of 22 m/min, and an 8 degrees grade. L-NNA was discontinued 5 days before 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 aortas of Sed-NA mice manifested a threefold increase in lesion formation compared with the other groups. This L-NNA-induced lesion formation was reduced by chronic exercise training (Sed, 786 +/- 144; Ex, 780 +/- 206; Sed-NA, 2,147 +/- 522; Ex-NA, 851 +/- 253; Sed-NA vs. all other groups: P < 0.001). In conclusion, treatment with oral L-NNA (an nitric oxide synthase antagonist) leads to accelerated atherogenesis in genetically determined hypercholesterolemic mice. This adverse effect can be overcome by chronic exercise training.
Niebauer
Josef
J
Vascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5246, USA.
Maxwell
Andrew J
AJ
Lin
Patrick S
PS
Wang
David
D
Tsao
Philip S
PS
Cooke
John P
JP
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005081:Exercise Therapy; D005260:Female; D006614:Hindlimb; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D005082:Physical Exertion / Q000502:physiology*
D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D019335:Nitroarginine; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D002950:Citrate (si)-Synthase