Abstract 17705: VSMC-specific Genetic Deletion of NoxA1, a Regulatory Subunit of Nox1 NADPH Oxidase, Attenuates Vascular Inflammation and Atherosclerosis in ApoE-/- Mice
Oxidative stress-induced activation of vascular smooth muscle cells (VSMC) is a key step in the initiation and progression of inflammation and atherogenesis and a potential target for therapy. We previously reported that NoxA1-dependent NADPH oxidase regulates atherogenesis in hypercholesterolemic conditions in studies comparing atherosclerosis in ApoE-/- and ApoE/NoxA1 double knockout mice. The therapeutic strategy of global inhibition of NoxA1 for atherosclerosis is potentially problematic because NoxA1 is reportedly not only expressed in VSMC but also in endothelial cells, liver, pancreas, and intestinal cells. Thus, to determine whether NoxA1 inhibition solely in VSMC was sufficient to reduce atherosclerosis, we developed SM22-CreKI/NoxA1f/f/ApoE-/- and ApoE-Cre+/- mice and compared atherosclerosis in these mice following 3 months of high-fat diet.
Total aortic atherosclerotic lesion size was reduced by 44% in SM22-CreKI/NoxA1f/f/ApoE-/- compared with ApoE-Cre+/- mice (p < 0.05). ROS levels in the aortic wall, measured by DHE fluorescence, were significantly lower in the SM22-CreKI/NoxA1f/f/ApoE-/- mice (p < 0.05). TNF-α induced H2O2 levels were also significantly reduced in VSMCs from SM22-CreKI/NoxA1f/f compared with wild-type VSMC (p <0.05). TNF-α induced DNA synthesis was reduced in SM22-CreKI/NoxA1f/f VSMC mice (p < 0.05 vs wild-type). In addition, SM22-CreKI/NoxA1f/f/ApoE-/- mice had decreased expression of VCAM1 in the aortic wall and decreased inflammatory CD11b+ macrophages, CD3+ T-lymphocytes, and c-kit+ mast cells in atherosclerotic lesions. TNF-α-induced expression of MAP kinase kinase kinase kinase 4 (MAP4K4), an upstream regulator of JNK1/2, and VCAM1 levels were decreased in SM22-CreKI/NoxA1f/f VSMC compared with the wild-type VSMC (p<0.05). Similarly, TNF-α-induced activation of redox-sensitive MAP kinases and JAK2 was reduced in these NoxA1 deficient VSMC.
These data indicate that VSMC-specific deletion of NoxA1 is sufficient to inhibit diet-induced atherosclerosis in ApoE-/- mice and suggest that specific VSMC NADPH oxidase inhibition may achieve reduced atherosclerosis without adverse effects related to NADPH oxidase inhibition systemically.
Author Disclosures: A. Sumida: None. A. Vendrov: None. J. Yuan: None. Q. Sun: None. N. Madamanchi: None. M. Runge: None.
- © 2014 by American Heart Association, Inc.