Korda, Mykhaylo and Kubant, Ruslan and Patton, Stephen and Malinski, Tadeusz (2008) Leptin-induced endothelial dysfunction in obesity. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 295 (4). H1514-H1521.
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Official URL: http://ajpheart.physiology.org/cgi/content/abstrac...
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.
|Subjects:||Analytical Science > Nanotechnology for sensing and actuating|
Biomedical Science > Nanotechnology for human health
Biomedical Science > Nanomedicine
|Deposited By:||Anuj Seth|
|Deposited On:||16 Dec 2008 14:32|
|Last Modified:||19 Jan 2009 12:10|
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