Leptin-induced endothelial dysfunction in obesity

被引:153
|
作者
Korda, Mykhaylo [1 ]
Kubant, Ruslan [1 ]
Patton, Stephen [1 ]
Malinski, Tadeusz [1 ]
机构
[1] Ohio Univ, Dept Chem & Biochem, Athens, OH 45701 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2008年 / 295卷 / 04期
关键词
nitric oxide; endothelium; leptin; nitroxidative stress;
D O I
10.1152/ajpheart.00479.2008
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Hyperleptinemia accompanying obesity affects endothelial nitric oxide ( NO) and is a serious factor for vascular disorders. NO, superoxide (O-2(-)), and peroxynitrite (ONOO-) nanosensors were placed near the surface (5 +/- 2 mu 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)-stimulated NO, O-2(-), 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, O-2(-), 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/1 control) and dramatically increased cytotoxic O-2(-) 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/1 control), and an elevated concentration of O-2(-) (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.
引用
收藏
页码:H1514 / H1521
页数:8
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