Low glucose induces mitochondrial reactive oxygen species via fatty acid oxidation in bovine aortic endothelial cells

Aims/Introduction Overproduction of reactive oxygen species ( ROS ) in endothelial cells ( EC s) plays a pivotal role in endothelial dysfunction. Mitochondrial ROS (mt ROS ) is one of the key players in the pathogenesis of diabetic vascular complications. Hypoglycemia is linked to increased ROS production and vascular events; however, the underlying mechanisms remain unclear. In the present study, we aimed to determine whether and how low glucose ( LG ) mediates mt ROS generation in EC s, and to examine the impact of LG ‐induced mt ROS on endothelial dysfunction. Materials and Methods Metabolomic profiling, cellular oxygen consumption rate, mt ROS , endothelial nitric oxide synthase phosphorylation, and the expression of vascular cell adhesion molecule‐1 or intercellular adhesion molecule‐1 were evaluated in bovine aortic EC s. Results We found that LG increased mt ROS generation in EC s; which was suppressed by overexpression of manganese superoxide dismutase. Comprehensive metabolic analysis using capillary electrophoresis‐mass spectrometry and oxygen consumption rate assessment showed that the pathway from fatty acid to acetyl‐CoA through fatty acid oxidation was upregulated in EC s under LG conditions. In addition, etomoxir, a specific inhibitor of the free fatty acid transporter, decreased LG ‐induced mt ROS production. These results suggested that LG increased mt ROS generation through activation of fatty acid oxidation. We further revealed that LG inhibited endothelial nitric oxide synthase phosphorylation, and increased the expression of vascular cell adhesion molecule‐1 and intercellular adhesion molecule‐1. These effects were suppressed either by overexpression of manganese superoxide dismutase or by treatment with etomoxir. Conclusions The activation of fatty acid oxidation followed by mt ROS production could be one of the causes for endothelial dysfunction during hypoglycemia.