Background: The NADPH oxidase organizer 1 (NoxO1) is an essential subunit of the NADPH oxidase 1 (Nox1) and serves as scaffolding protein of the activated protein complex. All members of the Nox family, including Nox1, generate reactive oxygen species (ROS) as main function. Nox derived ROS contribute to the cell’s redox status; imbalance of ROS production leads to cellular dysfunctions. In the vasculature Nox1 was found to impact diabetic dysfunctions, hypertension and vascular injury, but its role in atherosclerosis development remains unclear.  In this study we set out to determine the function of Nox1 in spontaneous atherosclerosis using a NoxO1 knockout approach.

Methods and results: Spontaneous atherosclerosis was induced by high fat diet combined with adenoviral overexpression of PCSK9 (Proprotein convertase subtilisin/kexin type 9), a mediator of LDL-receptor recycling. To determine contribution of Nox1/NoxO1 system in formation of atherosclerosis, female and male NoxO1 knockout mice were studied. Deletion of NoxO1 reduced plaque development in brachiocephalic artery and aortic arch of female mice significantly. MACEseq of abdominal aorta revealed only small differences in gene expression of relevant genes. Cytokine array of plasma samples indicated a significant anti-inflammatory signature after loss of NoxO1 in females only. Increase in IL-4 and decrease in IL-1 beta, Leptin and Leptin receptor levels were detected after NoxO1 deletion.

Conclusions: Deletion of the organizer protein NoxO1 limits atherosclerosis development and provokes induction of systemic anti-inflammatory processes in female mice.