title: Genetic deficiency of inducible nitric oxide synthase reduces atherosclerosis and lowers plasma lipid peroxides in apolipoprotein E-knockout mice.
abstract: BACKGROUND
  Inducible nitric oxide synthase (iNOS) is expressed by leukocytes and smooth muscle cells in atherosclerotic lesions. To test whether NO produced by iNOS deficiency affects atherosclerosis, we studied apoE/iNOS-double knockout (dKO) and apoE-knockout (KO) control animals fed a "Western-type" diet.
  
  
  RESULTS
  After 16 weeks of Western-type diet, the aortic lesion area in apoE/iNOS-dKO males and females was significantly reduced, by 22% and 21%, respectively, compared with apoE-KO males and females. This effect was more pronounced after 24 weeks of Western-type diet, after which lesion formation in male and female dKO mice was reduced by 38% and 40%, respectively. Plasma levels of lipoperoxides in apoE/iNOS-dKO mice (2.0+/-0.23 micromol/L) were significantly lower than in apoE-KO control animals (3.2+/-0.44 micromol/L; P=0.02). To test whether substrate deficiency plays a role in the proatherogenic actions of iNOS, we administered L-arginine to apoE-KO animals for 16 and 24 weeks. L-Arginine treatment did not affect lesion formation in apoE-KO animals fed a Western-type diet.
  
  
  CONCLUSIONS
  Genetic deficiency of iNOS decreases diet-induced atherosclerosis and lowers plasma levels of lipoperoxides, a marker for oxidative stress, in apoE-KO animals. Reduction in iNOS-mediated oxidative stress could partly explain protection from lesion formation in dKO animals. L-Arginine supplementation did not change lesion area in apoE-KO mice, indicating that substrate deficiency is not a likely cause for iNOS-mediated injury in this model of atherosclerosis.
authors: Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
authors: P J
authors: PJ
authors: Kuhlencordt
authors: J
authors: J
authors: Chen
authors: F
authors: F
authors: Han
authors: J
authors: J
authors: Astern
authors: P L
authors: PL
authors: Huang
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D001120:Arginine / Q000494:pharmacology; D001161:Arteriosclerosis / Q000473:pathology*; D004041:Dietary Fats / Q000008:administration & dosage; D019587:Dietary Supplements; D005260:Female; D005838:Genotype; D008054:Lipid Peroxides / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II
chemical_list: D001057:Apolipoproteins E; D004041:Dietary Fats; D008054:Lipid Peroxides; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse