The adipokine chemerin has been implicated in cardiovascular complications associated with obesity and the metabolic syndrome. Chemerin has direct effects on the vasculature, augmenting vascular responses to contractile stimuli. As NO/cGMP signalling plays a role in vascular dysfunction associated with obesity and the metabolic syndrome, we hypothesized that chemerin induces vascular dysfunction by decreasing NO/cGMP signalling. Aortic rings from male Wistar rats (10–12 weeks of age) were incubated with chemerin (0.5 or 5 ng/ml for 1 h) or vehicle and isometric tension was recorded. Vasorelaxation in response to ACh (acetylcholine), SNP (sodium nitroprusside) and BAY 412272 [an sGC (soluble guanylate cyclase) stimulator] were decreased in chemerin-treated vessels. The NOS (NO synthase) cofactor BH4 (tetrahydrobiopterin), an O2− (superoxide anion) scavenger (tiron) and a SOD (superoxide dismutase) mimetic (tempol) abolished the effects of chemerin on ACh-induced vasodilation. eNOS (endothelial NOS) phosphorylation, determined by Western blotting, was increased in chemerin-treated vessels; however, the enzyme was mainly in the monomeric form, with decreased eNOS dimer/monomer ratio. Chemerin decreased the mRNA levels of the rate-limiting enzyme for BH4 biosynthesis GTP cyclohydrolase I. Chemerin-incubated vessels displayed decreased NO production, along with increased ROS (reactive oxygen species) generation. These effects were abrogated by BH4, tempol and L-NAME (NG-nitro-L-arginine methyl ester). sGC protein expression and cGMP levels were decreased in chemerin-incubated vessels. These results demonstrate that chemerin reduces NO production, enhances NO breakdown and also decreases NO-dependent cGMP signalling, thereby reducing vascular relaxation. Potential mechanisms mediating the effects of chemerin in the vasculature include eNOS uncoupling, increased O2− generation and reduced GC activity.
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Research Article|
March 28 2014
Chemerin reduces vascular nitric oxide/cGMP signalling in rat aorta: a link to vascular dysfunction in obesity?
Karla Bianca Neves;
*Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil
†Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
Correspondence: Ms Karla Bianca Neves (email [email protected]).
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Núbia S. Lobato;
Núbia S. Lobato
‡Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil
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Rhéure Alves Moreira Lopes;
Rhéure Alves Moreira Lopes
†Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
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Fernando P. Filgueira;
Fernando P. Filgueira
†Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
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Camila Ziliotto Zanotto;
Camila Ziliotto Zanotto
‡Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil
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Ana Maria Oliveira;
Ana Maria Oliveira
*Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil
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Rita C. Tostes
Rita C. Tostes
†Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
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Publisher: Portland Press Ltd
Received:
July 30 2013
Revision Received:
January 13 2014
Accepted:
February 06 2014
Accepted Manuscript online:
February 06 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 127 (2): 111–122.
Article history
Received:
July 30 2013
Revision Received:
January 13 2014
Accepted:
February 06 2014
Accepted Manuscript online:
February 06 2014
Citation
Karla Bianca Neves, Núbia S. Lobato, Rhéure Alves Moreira Lopes, Fernando P. Filgueira, Camila Ziliotto Zanotto, Ana Maria Oliveira, Rita C. Tostes; Chemerin reduces vascular nitric oxide/cGMP signalling in rat aorta: a link to vascular dysfunction in obesity?. Clin Sci (Lond) 1 July 2014; 127 (2): 111–122. doi: https://doi.org/10.1042/CS20130286
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