Visfatin impairs endothelium-dependent relaxation in rat and human mesenteric microvessels through nicotinamide phosphoribosyltransferase activity
EntityUAM. Departamento de Farmacología; UAM. Departamento de Medicina
PublisherPublic Library of Science
10.1371/journal.pone.0027299Plos One 6.11 (2011): e27299
Funded byThis work was supported by grants from Ministerio de Ciencia e Innovación (SAF2008–01291, SAF2008–00942, SAF2011–28011 and SAF2011–24648) and Instituto de Salud Carlos III (RETICEF RD06/0013, PI061779)
SubjectsAcetylcholine; Endothelium, Vascular; Mesentery; Nicotinamide Phosphoribosyltransferase; Rats; Vasodilation; Medicina
Rights© 2011 Vallejo et al.
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
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
Google Scholar:Vallejo, Susana - Romacho, Tania - Angulo, Javier - Villalobos, Laura A. - Cercas, Elena - Leivas, Alejandra - Bermejo, Elena - Carraro, Raffaele - Sánchez Ferrer, Carlos Félix - Peiró Vallejo, M. Concepción
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The angiotensin-(1-7)/Mas receptor axis protects from endothelial cell senescence via klotho and Nrf2 activation Romero, Alejandra; San Hipólito-Luengo, Álvaro; Villalobos, Laura A.; Vallejo, Susana; Valencia, Inés; Michalska, Patrycja; Pajuelo-Lozano, Natalia; Sánchez Pérez, María Isabel; León, Rafael; Bartha Rasero, José Luis; Sanz, María Jesús; Erusalimsky, Jorge D.; Sánchez Ferrer, Carlos Félix; Romacho, Tania; Peiró Vallejo, M. Concepción