Leptin induces oxidative stress in human endothelial cells

Human umbilical vein endothelial cells (HUVEC) express functional receptors to leptin, the product of the ob gene. As human obesity is associated with atherosclerosis and hyperleptinemia, we investigated whether leptin, in ad dition to its angiogenic properties, exerts atherogenic effects through the generation of oxidative stress in endothelial cells. In HUVEC leptin incre ased the accumulation of reactive oxygen species (ROS), as assessed by the oxidation of 2',7'- dichlorodihydrofluorescein, in a time- and concentratio n-dependent manner. In addition, leptin activated the NH2-terminal c-Jun ki nase/stress-activated protein kinase pathway as demonstrated by enhanced JN K activity and AP-1 DNA binding. Both effects were sensitive to antioxidant treatment with N-acetylcysteine, NF-KB, another redox-sensitive transcript ion factor, was also activated by leptin stimulation in an oxidant-dependen t manner, Finally, activation of both AP-1 and NF-KB was associated with an enhanced expression of the monocyte chemoattractant protein-1 in HUVEC, Th ese findings demonstrate that ROS are second messengers involved in leptin- induced signaling in endothelial cells. Thus, chronic oxidative stress in e ndothelial cells under hyperleptinemia may activate atherogenic processes a nd contribute to the development of vascular pathology.