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. 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 (2.0Ϯ0.23 mol/L) were significantly lower than in apoE-KO control animals (3.2Ϯ0.44 mol/L; Pϭ0.02). 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.

Curcumin inhibits LPS-induced inflammation in rat vascular smooth muscle cells in vitro via ROS-relative TLR4-MAPK/NF-κB pathways

“…In vivo experiments using ApoE -/-mice having reduced levels of iNOS reported fewer instances of atherosclerosis and lower levels of plasma lipid peroxides than mice with normal iNOS levels. Furthermore, ONO1714, a selective inhibitor of iNOS, was found to retard atherosclerosis induced by a high-cholesterol diet [39,40] . These results imply that inhibiting the overexpression of iNOS and the subsequent overproduction of NO may help slow the progression of atherosclerosis.…”

Lipoxygenase Products Regulate Nitric Oxide and Inducible Nitric Oxide Synthase Production in Interleukin-1.BETA. Stimulated Vascular Smooth Muscle Cells.

“…iNOS may contribute to lesion formation by increasing oxidative stress in the vessel wall (29). Genetic deficiency of iNOS decreases Western-type diet-induced atherosclerosis in apolipoprotein E (apo E)-genedeficient mice (12). On the other hand, the sPLA2 and LOX enzymes also can be induced by inflammatory cytokines.…”

“…Therefore, regulation of iNOS gene expression has also been implicated in the pathogenesis of vascular remodeling and atherosclerosis (8)(9)(10)(11). Recently, the significance of iNOS in the pathogenesis of atherosclerosis was demonstrated by studies of genetic deficiency of iNOS in apo E-gene deficient mice (12).…”

iNOS-Derived Nitric Oxide Induces Integrin-Linked Kinase Endocytic Lysosome-Mediated Degradation in the Vascular Endothelium

“…Because iNOS-mediated NO formation has been linked to the development of atherosclerosis, 17,18 ILK and iNOS levels were studied in endarterectomy specimens of human carotid arteries (n=25) showing varying degrees of atherosclerosis (plaque) and in human arterial specimens free of atherosclerosis as controls (healthy, n=20). Confirming our earlier observations, 6 Western blot analysis revealed a significant decrease in total ILK expression in atherosclerotic carotid arteries versus healthy vessels ( Figure 1A).…”