Leptin-induced endothelial dysfunction in obesity

Abstract

Hyperleptinemia accompanying obesity affects endothelial nitric oxide (NO) and is a serious factor for vascular disorders. NO, superoxide (O 2 Ϫ ), and peroxynitrite (ONOO Ϫ ) nanosensors were placed near the surface (5 Ϯ 2 m) 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) (14,32). Endothelial dysfunction has been associated with several vascular diseases (32). Bioavailable nitric oxide (NO) production is diminished in dysfunctional endothelium, which hinders the L-arginine/NO pathway and increases vasoconstriction (13).-There have been several reports suggesting the potential mechanisms for diminished NO production in obesity. It has been proposed that the elevated free fatty acids levels observed in obesity may inhibit endothelial NO synthase (eNOS) (8). Also, the increased levels of cytokines IL-6 and TNF-␣ observed in obesity may affect the phosphorylation of tyrosine kinases and eNOS expression (16). It also has been suggested that obesity is associated with an increased production of reactive oxygen species in the cardiovascular system (31).Recent evidence indicates that adipose tissue-derived hormone leptin can be involved in vascular tone control (1, 7) and that leptin receptors (Ob-R) are expressed in endothelial cells (4). In a vascular ring model, leptin induced vasorelaxation in a dose-dependent manner, and this effect was abolished by eNOS inhibitors (18,19). The in vitro stimulatory effect of leptin on NO production in cultured endothelial cells was also tested by measuring nitrite and nitrate concentrations (30). The intravenous injection of leptin increased nitrite and nitrate concentrations in blood serum of normotensive Wistar rats but not in obese Zucker rats, which have a mutation in their leptin receptor gene (12). Intraperitoneal leptin administration also increased plasma concentration and urinary excretion of NO metabolites, as well as NO second messenger, guanosine 3Ј,5Ј-cyclic monophosphate (cGMP) (3). All this data indirectly indicate that leptin may increase NO production in endothelial cells and cause these hypotensive effects. It has also been shown that stimulation of endothelial cells with leptin leads to an increase in the production of reactive oxygen species, in particular superoxide (O 2 Ϫ ), which is known to react rapidly with NO to form peroxynitrite (ONOO Ϫ ) (5, 35). The leptin level increases in obesity (7), but the long-term effect of elevated leptin on the bioavailability of endothelial NO and cytotoxic ONOO Ϫ is not known. This work was designed to clarify the potential role of NO, O 2 Ϫ , and ONOO Ϫ in leptin-associated vascular disorders associated with obesity. A system of nanosensors was used for direct simultaneous measurements of the leptin-induced biosynthesis of NO, O 2 Ϫ , and ONOO Ϫ in human umbilical vein endothelial cell (HUVEC) or the endothelium of obese mice. METHODSAll materials were purchased from Sigma-Aldrich (St. Louis, MO), unl...

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