Abstract 14725: The Roles of Smooth Muscle Nox4 in Atherosclerosis and Restenosis
Introduction: Elevated levels of reactive oxygen species (ROS) in the vascular wall play a key role in the development of atherosclerosis and stenosis. Nox4 based NADPH oxidases are the major ROS generating enzymes in the vasculature, but its roles in atherosclerosis and stenosis remain unclear.
Methods: Mouse lines to overexpress human Nox4 dominant negative form P437H (Nox4DN) in smooth muscle driven by the SM22-alpha promoter were characterized in a FVB/N background. Non-transgenic littermate mice (NTg) were used as controls. These Nox4DN mice were backcrossed into FVB/N ApoE deficient background for atherosclerotic lesion analysis.
Results: In FVB/N background, Nox4DN significantly decreased ROS production, serum induced proliferation and migration, and macrophage adhesion in aortic SMCs compared with NTg. Nox4DN modestly but significantly decreased blood pressure. In a wire injury induced endothelial denudation model, Nox4DN significantly decreased neointima formation. In FVB/N ApoE deficient background, Nox4DN significantly decreased western diet induced aortic root lesions and aortic pulse wave velocity. Gene expression assays indicated that soluble epoxide hydrolase 2 (sEH) and thrombospondin 1 (TSP1) were significantly downregulated in Nox4DN, which were furthered confirmed in protein levels. In NTg SMCs, downregulation of either sEH or TSP1 decreased cell proliferation and migration, but only downregulation of sEH suppressed inflammation and macrophage adhesion. Downregulation of TSP1 had no effect on sEH, while knockdown of sEH decreased TSP1, indicating that sEH can directly regulate TSP1.
Conclusion: Downregulation of smooth muscle Nox4 inhibits restenosis and atherosclerosis by suppressing sEH, which inhibits SMC proliferation, migration and inflammation.
- © 2013 by American Heart Association, Inc.