title: Visfatin impairs endothelium-dependent relaxation in rat and human mesenteric microvessels through nicotinamide phosphoribosyltransferase activity.
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.
authors.affiliation: Departamento de Farmacología, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Vallejo
authors.forename: Tania
authors.initials: T
authors.lastname: Romacho
authors.forename: Javier
authors.initials: J
authors.lastname: Angulo
authors.forename: Laura A
authors.initials: LA
authors.lastname: Villalobos
authors.forename: Elena
authors.initials: E
authors.lastname: Cercas
authors.forename: Alejandra
authors.initials: A
authors.lastname: Leivas
authors.forename: Elena
authors.initials: E
authors.lastname: Bermejo
authors.forename: Raffaele
authors.initials: R
authors.lastname: Carraro
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Sánchez-Ferrer
authors.forename: Concepción
authors.initials: C
authors.lastname: Peiró
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D008643:Mesentery / Q000098:blood supply*; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism* / Q000502:physiology*; D051381:Rats; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D054409:Nicotinamide Phosphoribosyltransferase; D000109:Acetylcholine
references.citation: Hypertens Res. 2011 Jan;34(1):5-14
references.pmid: 20981034
references.citation: Clin Endocrinol (Oxf). 2009 Aug;71(2):202-7
references.pmid: 19178507
references.citation: J Nephrol. 2011 Mar-Apr;24(2):177-84
references.pmid: 20602330
references.citation: Biochem Biophys Res Commun. 2009 Jun 12;383(4):503-8
references.pmid: 19393628
references.citation: Cell Metab. 2007 Nov;6(5):363-75
references.pmid: 17983582
references.citation: Int J Mol Med. 2011 Apr;27(4):607-15
references.pmid: 21327328
references.citation: Exp Clin Endocrinol Diabetes. 2010 Feb;118(2):75-80
references.pmid: 19834878
references.citation: J Endocrinol Invest. 2007 Apr;30(4):323-6
references.pmid: 17556870
references.citation: Science. 2007 Oct 26;318(5850):565
references.pmid: 17962537
references.citation: Int J Obes (Lond). 2009 Apr;33(4):465-72
references.pmid: 19223849
references.citation: J Immunol. 2011 Jun 1;186(11):6474-84
references.pmid: 21518975
references.citation: Aging Cell. 2009 Jun;8(3):226-38
references.pmid: 19245678
references.citation: Nephrology (Carlton). 2010 Mar;15(2):190-6
references.pmid: 20470278
references.citation: Biochem J. 1987 Feb 15;242(1):123-9
references.pmid: 2439067
references.citation: Diabetologia. 2003 Apr;46(4):556-66
references.pmid: 12739028
references.citation: Transplant Proc. 2009 Jan-Feb;41(1):150-3
references.pmid: 19249500
references.citation: Mol Cell Biol. 1994 Feb;14(2):1431-7
references.pmid: 8289818
references.citation: J Clin Endocrinol Metab. 2006 Jan;91(1):295-9
references.pmid: 16234302
references.citation: Kidney Int. 2010 Jul;78(2):170-81
references.pmid: 20375985
references.citation: Biochim Biophys Acta. 2008 May;1783(5):886-95
references.pmid: 18241674
references.citation: Diabetes Care. 2008 Apr;31(4):758-60
references.pmid: 18184904
references.citation: Cardiovasc Res. 2009 Feb 1;81(2):370-80
references.pmid: 18952695
references.citation: Am J Physiol Endocrinol Metab. 2009 Jun;296(6):E1440-9
references.pmid: 19351806
references.citation: Science. 2005 Jan 21;307(5708):426-30
references.pmid: 15604363
references.citation: Pflugers Arch. 2010 May;459(6):923-39
references.pmid: 20306272
references.citation: Clin Transplant. 2009 Mar-Apr;23(2):241-8
references.pmid: 19402217
references.citation: Metabolism. 2007 Apr;56(4):451-8
references.pmid: 17378999
references.citation: Nephrol Dial Transplant. 2008 Mar;23(3):959-65
references.pmid: 17984105
references.citation: J Atheroscler Thromb. 2010 Feb 26;17(2):115-30
references.pmid: 20145358
references.citation: PLoS One. 2010 Apr 08;5(4):e10091
references.pmid: 20386708
references.citation: Eur J Immunol. 2002 Nov;32(11):3225-34
references.pmid: 12555668
references.citation: Diabetologia. 2009 Nov;52(11):2455-2463
references.pmid: 19727662
references.citation: Cardiovasc Res. 2011 Feb 1;89(2):401-9
references.pmid: 20823276