Abstract 18616: NoxA1-Dependent NADPH Oxidase Regulates VSMC Phenotype, Hypertension, and Atherosclerosis

Increased oxidative stress and inflammation are key components in the pathogenesis of atherosclerosis and hypertension. We previously reported that Nox activator 1 (NoxA1) is the functional homolog of p67phox in Nox1 NADPH oxidase activation in mouse vascular smooth muscle cells (VSMCs), and its mRNA and protein expression are induced by TNF-α, a proinflammatory cytokine. Here we investigated the physiological function of NoxA1-dependent NADPH oxidase activity in mouse VSMCs, and NoxA1 expression in human aortic SMCs (HASMCs), in response to TNF-α. Furthermore, we evaluated the role of this enzyme in angiotensin II-mediated hypertension and in atherogenesis in ApoE -/- mice. TNF-α-induced ROS generation was significantly attenuated in NoxA1 -/- VSMCs compared with the wild-type (p <0.05). NoxA1 deletion also significantly decreased TNF-α-induced DNA synthesis and migration in mouse VSMCs (p <0.05 in each case). In HASMCs, NoxA1 mRNA expression was 10-fold higher than that of p67phox, and NoxA1 mRNA and protein expression were markedly induced by TNF-α (p>0.05 in each case). Angiotensin II infusion for 2 weeks significantly increased systolic blood pressure in wild-type mice, but this response was attenuated in NoxA1 -/- mice. Atherosclerotic lesion size was reduced by 50% in ApoE -/- /NoxA1 -/- compared with ApoE -/- in mice that were fed Western diet for three months. ROS levels in the aortic wall of ApoE -/- /NoxA1 -/- were significantly lower compared with ApoE -/- mice. In addition, ApoE -/- /NoxA1 -/- mice had less accumulation of inflammatory CD11b + macrophages, CD3 + T-lymphocytes, and c-kit + mast cells in atherosclerotic lesions. In conclusion, NoxA1-dependent NADPH oxidase regulates oxidative stress, inflammation, angiotensin II-induced hypertension, and atherogenesis in hypercholesterolemic mice, suggesting that selective targeting of NoxA1 is beneficial.