Abstract
Visfatin, also known as extracellular pre–B-cell colony–enhancing factor (PBEF) and nicotinamide phosphoribosyltransferase (Nampt), is an adipocytokine whose circulating levels are enhanced in metabolic disorders, such as type 2 diabetes mellitus and obesity. Circulating visfatin levels have been positively associated with vascular damage and endothelial dysfunction. Here, we investigated the ability of visfatin to directly impair vascular reactivity in mesenteric microvessels from both male Sprague-Dawley rats and patients undergoing non-urgent, non-septic abdominal surgery. The pre-incubation of rat microvessels with visfatin (50 and 100 ng/mL) did not modify the contractile response to noradrenaline (1 pmol/L to 30 µmol/L), as determined using a small vessel myograph. However, visfatin (10 to 100 ng/mL) concentration-dependently impaired the relaxation to acetylcholine (ACh; 100 pmol/L to 3 µmol/L), without interfering with the endothelium-independent relaxation to sodium nitroprusside (1 nmol/L to 3 µmol/L). In both cultured human umbilical vein endothelial cells and rat microvascular preparations, visfatin (50 ng/mL) stimulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, as determined by lucigenin-derived chemiluminiscence. The relaxation to ACh impaired by visfatin was restored by the NADPH oxidase inhibitor apocynin (10 µmol/L). Additionally, the Nampt inhibitor APO866 (10 mmol/L to 10 µmol/L), but not an insulin receptor-blocking antibody, also prevented the stimulation of NADPH oxidase and the relaxation impairment elicited by visfatin. Accordingly, the product of Nampt activity nicotinamide mononucleotide (100 nmol/L to 1 mmol/L) stimulated endothelial NADPH oxidase activity and concentration-dependently impaired ACh-induced vasorelaxation. In human mesenteric microvessels pre-contracted with 35 mmol/L potassium chloride, the endothelium-dependent vasodilation to bradykinin (1 nmol/L to 3 µmol/L) was equally impaired by visfatin and restored upon co-incubation with APO866. In conclusion, visfatin impairs endothelium-dependent relaxation through a mechanism involving NADPH oxidase stimulation and relying on Nampt enzymatic activity, and therefore arises as a potential new player in the development of endothelial dysfunction.
Highlights
In 2005, visfatin was identified as a novel adipocytokine preferently released by visceral fat and exhibiting insulin-mimetic properties [1]
To gain insight into the mechanisms mediating the impaired endothelium-dependent vasodilation induced by visfatin in rat microvessels, we explored the impact of the adipokine on nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, considered as a major mechanism involved in endothelial dysfunction [12,13]
Endothelial dysfunction, which can be defined as the loss of balance between the multiple factors controlling reactivity, inflammation, coagulation and cell growth at the vascular level, is a key event tightly associated to the development of vascular diseases, including atherosclerosis and coronary artery disease
Summary
In 2005, visfatin was identified as a novel adipocytokine preferently released by visceral fat and exhibiting insulin-mimetic properties [1]. This latter statement, was retracted due to reproducibility concerns on the hypoglycemic properties of visfatin [2]. Several observations have suggested a direct association between plasma visfatin levels and endothelial dysfunction. A negative association has been found between circulating visfatin levels and brachial artery flow-mediated dilation (FMD), used as a non-invasive measurement of endothelial function in humans [7,9,10]. In patients undergoing renal transplantation, visfatin has been identified as a strong predictor of FMD and the reduction of plasma visfatin levels following transplantation is accompanied by the normalization of the endothelial function [11]
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