Leptin-induced endothelial dysfunction in obesity
- 1 October 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 295 (4), H1514-H1521
- https://doi.org/10.1152/ajpheart.00479.2008
Abstract
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.Keywords
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