Deficiency of inducible NO synthase reduces advanced but not early atherosclerosis in apolipoprotein E-deficient mice

Toru Miyoshi, Yuhua Li, Diana M. Shih, Xuping Wang, Victor E. Laubach, Alan H. Matsumoto, Gregory A. Helm, Aldons J. Lusis, Weibin Shi

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

The inducible nitric oxide synthase (iNOS) is abundantly expressed by smooth muscle cells and macrophages in atherosclerotic lesions. Apolipoprotein E-deficient (apoE-/-) mice develop early and advanced atherosclerotic lesions. The role of iNOS in both early and advanced atherosclerotic formation was determined in apoE-/- mice. Mice were fed chow or a Western diet containing 42% fat, 0.15% cholesterol, and 19.5% casein. At 12 weeks of age on chow diet, iNOS-/-/apoE-/- mice developed comparable sizes of early atherosclerotic lesions in the aortic root as did iNOS+/+/apoE-/- mice (30,993 ± 4746 vs. 26,648 ± 6815 μm2/section; P = 0.608). After being fed the Western diet for 12 weeks, iNOS-/-/apoE-/- mice developed significantly smaller advanced lesions than iNOS+/+/apoE-/- mice (458,734 ± 14,942 vs. 519,570 ± 22,098 μm2/section; P = 0.029). This reduction in lesion formation could not be explained by differences in plasma lipid levels. To examine whether iNOS contributed to LDL oxidation, smooth muscle cells were isolated from the aorta, activated with TNF-α, and then incubated with native LDL in the absence or presence of N-Ω-nitro-l-arginine methyl ester (L-NAME), a specific NOS inhibitor. L-NAME significantly inhibited LDL oxidation by smooth muscle cells from iNOS+/+/apoE-/- mice (P = 0.048), but it had no effect on LDL oxidation by cells from iNOS-/-/apoE-/- mice. iNOS-/-/apoE-/- mice had a significantly lower plasma lipoperoxide level on the Western diet (2.74 ± 0.23 vs. 3.89 ± 0.41 μM MDA; P = 0.021) but not on chow diet (1.02 ± 0.07 vs. 1.51 ± 0.29 μM MDA; P = 0.11). Thus, the absence of iNOS-mediated LDL oxidation may contribute to the reduction in advanced lesion formation of iNOS-/-/apoE-/- mice.

Original languageEnglish
Pages (from-to)525-531
Number of pages7
JournalLife Sciences
Volume79
Issue number6
DOIs
Publication statusPublished - Jul 4 2006
Externally publishedYes

Keywords

  • Atherosclerosis
  • Inducible nitric oxide synthase
  • LDL oxidation
  • Mice

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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