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.

Methods and 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 μmol/L) were significantly lower than in apoE-KO control animals (3.2±0.44 μmol/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.