Abstract 14915: Paradoxical Effect of Genetic Deletion of Nox2 in Endothelial-specific Insulin Resistant Mice on Development of Atherosclerosis
Global and endothelium-specific insulin resistance is associated with accelerated atherosclerosis and increased Nox2 NADPH oxidase derived superoxide. We therefore investigated the impact of genetic deletion of Nox2 in atherosclerosis prone ApoE-/- mice with endothelium-specific insulin resistance by cross-breeding mice expressing a dominant negative mutant human insulin receptor specifically in the endothelium (ESMIRO) with ApoE-/-/Nox2-/y mice. This generated 4 genotypes (ApoE-/-; ESMIRO/ApoE-/-; ApoE-/-/Nox2-/y; ESMIRO/ApoE-/-/Nox2-/y) Twenty-week-old male ESMIRO/ApoE-/-/Nox2-/y mice were compared to male ApoE-/-, ESMIRO/ApoE-/-, and ApoE-/-/Nox2-/y littermates after ad libitum feeding of high cholesterol western diet for 12 weeks. No differences were observed in mean body mass between the four groups. Blood pressure, fasting glucose, glucose tolerance, insulin sensitivity and plasma lipid profiles were also similar in all groups. However, en-face analysis (oil red O staining) of the aorta showed a significant increase in atherosclerotic lesion area in ESMIRO/ApoE-/-/Nox2-/y (n=16) mice, compared to ApoE-/- (n=17); ESMIRO/ApoE-/- (n=13) littermates (10.75%±1.28% versus 5.8%±0.56% versus 7.14%±0.94%, respectively, p<0.05), but not in comparison with ApoE-/-/Nox2-/y (n=12) littermates (8.81% %±1.46%, p>0.05). We observed evidence of suppurative granulomas in ESMIRO/ApoE-/-/Nox2-/y mice but not in other genotypes. Our observations demonstrate that genetic deletion of Nox2 aggravates atherosclerosis in atherosclerosis prone mice with endothelium-specific insulin resistance. These data suggest that therapeutic inhibition of Nox2 in insulin resistance may not retard atherosclerosis due to the generation of a chronic inflammatory environment
Author Disclosures: N.Y. Yuldasheva: None. A. Skromna: None. N. Makava: None. A. Maqbool: None. G. Nikanorova: None. R.M. Cubbon: None. S.B. Wheatcroft: None. M.T. Kearney: None.
- © 2016 by American Heart Association, Inc.