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Am J Physiol Heart Circ Physiol 295: H1514-H1521, 2008. First published August 8, 2008; doi:10.1152/ajpheart.00479.2008
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Leptin-induced endothelial dysfunction in obesity

Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio

Submitted 7 May 2008 ; accepted in final form 31 July 2008

Hyperleptinemia accompanying obesity affects endothelial nitric oxide (NO) and is a serious factor for vascular disorders. NO, superoxide (O₂^–), and peroxynitrite (ONOO^–) nanosensors were placed near the surface (5 ± 2 µm) of a single human umbilical vein endothelial cell (HUVEC) exposed to leptin or aortic endothelium of obese C57BL/6J mice, and concentrations of calcium ionophore (CaI)-stimulated NO, O₂^–, ONOO^– were recorded. Endothelial NO synthase (eNOS) expression and L-arginine concentrations in HUVEC and aortic endothelium were measured. Leptin did not directly stimulate NO, O₂^–, or ONOO^– release from HUVEC. However, a 12-h exposure of HUVEC to leptin increased eNOS expression and CaI-stimulated NO (625 ± 30 vs. 500 ± 24 nmol/l control) and dramatically increased cytotoxic O₂^– and ONOO^– levels. The [NO]-to-[ONOO^–] ratio ([NO]/[ONOO^–]) decreased from 2.0 ± 0.1 in normal to 1.30 ± 0.1 in leptin-induced dysfunctional endothelium. In obese mice, a 2.5-fold increase in leptin concentration coincided with 100% increase in eNOS and about 30% decrease in intracellular L-arginine. The increased eNOS expression and a reduced L-arginine content led to eNOS uncoupling, a reduction in bioavailable NO (250 ± 10 vs. 420 ± 12 nmol/l control), and an elevated concentration of O₂^– (240%) and ONOO^– (70%). L-Arginine and sepiapterin supplementation reversed eNOS uncoupling and partially restored [NO]/[ONOO^–] balance in obese mice. In obesity, leptin increases eNOS expression and decreases intracellular L-arginine, resulting in eNOS an uncoupling and depletion of endothelial NO and an increase of cytotoxic ONOO^–. Hyperleptinemia triggers an endothelial NO/ONOO^– imbalance characteristic of dysfunctional endothelium observed in other vascular disorders, i.e., atherosclerosis and diabetes.

nitric oxide; endothelium; leptin; nitroxidative stress