Abstract 591: Absence of Nicotinamide Nucleotide Transhydrogenase Exacerbates Atherosclerosis in Mice

Abstract

Oxidant stress contributes to endothelial cell injury and inflammation that are hallmarks of early stage atherosclerosis. Emerging evidence implicates mitochondrial reactive oxygen species (ROS) as important contributors to this oxidant stress and differences in mitochondrial function may augment this process. We have shown that variation in mitochondrial function and ROS production associated with ethnicity contributes to endothelial and vascular dysfunction. To model these distinct mitochondrial redox phenotypes we used C57Bl/6N (6N) and C57Bl/6J (6J) mice that also display unique mitochondrial functional properties due to the differential expression nicotinamide nucleotide transhydrogenase (NNT). Mice were treated with adeno-associated virus encoding a gain-of-function form of proprotein convertase subtilisin/kexin type 9 (PCSK9) that leads to hypercholesterolemia, increased LDL levels, and atherosclerosis in mice. PCSK9 treatment and 8 weeks of high fat diet led to increases in plasma lipids in both 6N and 6J mice. However, 6J animals displayed significantly higher levels of fat deposition in the vasculature and increased plaque size in the carotid sinus. 6N mice co-treated with the mitochondria targeted superoxide dismutase mimetic MitoTEMPO for the final 4 weeks of the experiment displayed reduced plasma lipids, but no impact on fat deposition or plaque size was observed. In contrast, MitoTEMPO increased vascular fat deposition and plaque size in 6J mice consistent with a more severe atherosclerotic phenotype. Increased mitochondrial ROS was confirmed by demonstrating elevated vascular superoxide in 6J versus 6N animals and that this difference is exacerbated on high fat diet. MitoTEMPO diminished vascular superoxide production to near baseline levels in both groups, yet increased plaque size and fat deposition in 6J mice suggests a role for hydrogen peroxide in this process. These data indicate that loss of NNT and changes in mitochondrial function increase vascular ROS production and exacerbate lipid deposition and plaque development in the early stages of atherosclerosis.