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Institut für Kardiovaskuläre Physiologie, Klinikum der J. W. Goethe-Universität, Frankfurt/Main, Germany; and
* INSERM U317, Institut Louis Bugnard, CHU Rangueil, Toulouse, France
1Correspondence: Institut für Kardiovaskuläre Physiologie, Klinikum der J. W. Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. E-mail: bouloumie{at}em.uni-frankfurt.de
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 addition to its angiogenic
properties, exerts atherogenic effects through the generation of
oxidative stress in endothelial cells. In HUVEC leptin increased the
accumulation of reactive oxygen species (ROS), as assessed by the
oxidation of 2',7'- dichlorodihydrofluorescein, in a time- and
concentration-dependent manner. In addition, leptin activated the
NH2-terminal c-Jun kinase/stress-activated protein kinase
pathway as demonstrated by enhanced JNK activity and AP-1 DNA binding.
Both effects were sensitive to antioxidant treatment with
N-acetylcysteine. NF-
B, another redox-sensitive transcription
factor, was also activated by leptin stimulation in an
oxidant-dependent manner. Finally, activation of both AP-1 and NF-B
was associated with an enhanced expression of the monocyte
chemoattractant protein-1 in HUVEC. These findings demonstrate that ROS
are second messengers involved in leptin-induced signaling in
endothelial cells. Thus, chronic oxidative stress in endothelial cells
under hyperleptinemia may activate atherogenic processes and contribute
to the development of vascular pathology.—Bouloumié, A., Marumo,
T., Lafontan, M., Busse, R. Leptin induces oxidative stress in human
endothelial cells.
Key Words: Jun kinase • MCP-1 • AP-1 • NF-B • atherosclerosis • obesity
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