Abstract 15081: NOX1-Deficiency in Apolipoprotein E-Knockout Mice is Associated with Elevated Plasma Lipids and Enhanced Atherosclerosis
NADPH oxidases (NOX) are unique in being the only enzymes with the primary function of generating reactive oxygen species (ROS). Seven mammalian isoforms of NADPH oxidase have been described, and four of these - NOX1, NOX2, NOX4 and NOX5 - are expressed in the vascular wall. Previous studies demonstrated that NOX2 activity in the vascular wall is elevated in conditions such as hypercholesterolemia and hypertension, and contributes to the excess ROS production that leads to oxidative stress, endothelial dysfunction and remodelling. In this study, we examined the role of another NOX isoform - NOX1 - in atherogenesis in apolipoprotein E-knockout (APOE-/-) mice maintained on a Western diet for 14 weeks. ROS production (measured by L012 chemiluminescence) was ∼2-fold higher in aortic rings from APOE-/- mice than in those from wild-types (P<0.05, n≥10). Real-time PCR studies demonstrated an increase in NOX2 expression in aortas from APOE-/- vs wild-type mice (P<0.05, n≥9); however, no change in NOX1 expression was observed. In fact, aortic expression of the NOX1-specific ‘organiser’ subunit, NOXO1, was reduced in APOE-/- mice, suggesting an overall reduction in NOX1 activity. To examine the impact of a further reduction in NOX1 activity, APOE-/- mice were crossed with NOX1-/- mice to generate NOX1-/-/APOE-/- double knockouts. NOX1-deficiency in APOE-/- mice was associated with 30-50% higher plasma VLDL/LDL and triglyceride levels (P<0.01, n=17), with no change in HDL. Vascular ROS levels were also unchanged in NOX1-/-/APOE-/- versus APOE-/- mice, as was the extent of atherosclerotic lesion coverage along the aorta revealed by en face analysis of oil red O-stained vessels. By contrast, histological analysis of cross sections through the aortic root showed that lesions in the double knockouts were ∼40% thicker (P<0.05, n=9) and contained ∼70% less collagen (P<0.05, n≥6) than those in APOE-/- mice. Thus, our data suggest a possible protective role for NOX1 against hyperlipidemia and atherosclerosis in APOE-/- mice. Although the mechanisms by which NOX1 affords protection remain unknown, our studies highlight the complex and potentially contrasting roles that ROS derived from different enzyme sources (e.g. NOX2 versus NOX1) may play in vascular pathophysiology.
- © 2012 by American Heart Association, Inc.