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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.

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