NOX1 deficiency in apolipoprotein E-knockout mice is associated with elevated plasma lipids and enhanced atherosclerosis.

AbstractNicotinamide adenine dinucleotide phosphate oxidases (NOX) are enzymes that generate reactive oxygen species (ROS). NOX2 activity in the vascular wall is elevated in hypercholesterolemia, and contributes to oxidative stress and atherogenesis. Here we examined the role of another NOX isoform, NOX1, in atherogenesis in apolipoprotein E-knockout (APOE−/−) mice fed a Western diet for 14 weeks. Although NOX1 mRNA expression was unchanged in aortas from APOE−/− versus wild-type mice, expression of the NOX1-specific organizer, NOXO1, was diminished, consistent with an overall reduction in NOX1 activity in APOE−/− mice. To examine the impact of a further reduction in NOX1 activity, APOE−/− mice were crossed with NOX1−/y mice to generate NOX1−/y/APOE−/− double-knockouts. NOX1 deficiency in APOE−/− mice was associated with 30–50% higher plasma very-low-density lipoprotein (VLDL)/LDL and triglyceride levels (P < 0.01). Vascular ROS levels were also elevated by twofold in NOX1−/y/APOE−/− versus APOE−/− mice (...