title: Chemerin Regulates Crosstalk Between Adipocytes and Vascular Cells Through Nox.
abstract: Adipocytes produce adipokines, including chemerin, a chemoattractant that mediates effects through its ChemR23 receptor. Chemerin has been linked to endothelial dysfunction and vascular injury in pathological conditions, such as obesity, diabetes mellitus, and hypertension. Molecular mechanisms underlying this are elusive. Here we assessed whether chemerin through redox-sensitive signaling influences molecular processes associated with vascular growth, apoptosis, and inflammation. Human microvascular endothelial cells and vascular smooth muscle cells were stimulated with chemerin (50 ng/mL). Chemerin increased generation of reactive oxygen species and phosphorylation of mitogen-activated protein kinases, effects that were inhibited by ML171, GKT137831 (Nox inhibitors), and N-acetylcysteine (reactive oxygen species scavenger). Chemerin increased mRNA expression of proinflammatory mediators in vascular cells and increased monocyte-to-endothelial cell attachment. In human vascular smooth muscle cells, chemerin induced phosphorylation of mitogen-activated protein kinases and stimulated proliferation (increased proliferating cell nuclear antigen expression [proliferation marker] and BrdU incorporation [proliferation assay]). Chemerin decreased phosphatidylinositol 3-kinase/protein kinase B activation and increased TUNEL-positive human vascular smooth muscle cells. In human microvascular endothelial cells, chemerin reduced endothelial nitric oxide synthase activity and nitric oxide production. Adipocyte-conditioned medium from obese/diabetic mice (db/db), which have elevated chemerin levels, increased reactive oxygen species generation in vascular smooth muscle cells, whereas adipocyte-conditioned medium from control mice had no effect. Chemerin actions were blocked by CCX 832, a ChemR23 inhibitor. Our data demonstrate that chemerin, through Nox activation and redox-sensitive mitogen-activated protein kinases signaling, exerts proapoptotic, proinflammatory, and proliferative effects in human vascular cells. These findings elucidate some molecular mechanisms through chemerin, which is increased in obesity, whereby adipocytes may influence vascular function. We identify chemerin as a novel vasoactive adipokine, which may be important in obesity-related vascular injury.
authors.affiliation: From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow (K.B.N., A.N.D.C., R.A.M.L., F.J.R., A.A., A.C.M., R.M.T.); Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N., A.M.d.O.) and Department of Pharmacology (R.A.M.L., R.C.T.), University of Sao Paulo, Ribeirao Preto, SP, Brazil; and Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil (N.S.L.).
authors.forename: Karla Bianca
authors.initials: KB
authors.lastname: Neves
authors.affiliation: From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow (K.B.N., A.N.D.C., R.A.M.L., F.J.R., A.A., A.C.M., R.M.T.); Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N., A.M.d.O.) and Department of Pharmacology (R.A.M.L., R.C.T.), University of Sao Paulo, Ribeirao Preto, SP, Brazil; and Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil (N.S.L.).
authors.forename: Aurelie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.affiliation: From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow (K.B.N., A.N.D.C., R.A.M.L., F.J.R., A.A., A.C.M., R.M.T.); Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N., A.M.d.O.) and Department of Pharmacology (R.A.M.L., R.C.T.), University of Sao Paulo, Ribeirao Preto, SP, Brazil; and Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil (N.S.L.).
authors.forename: Rheure Alves Moreira
authors.initials: RA
authors.lastname: Lopes
authors.affiliation: From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow (K.B.N., A.N.D.C., R.A.M.L., F.J.R., A.A., A.C.M., R.M.T.); Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N., A.M.d.O.) and Department of Pharmacology (R.A.M.L., R.C.T.), University of Sao Paulo, Ribeirao Preto, SP, Brazil; and Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil (N.S.L.).
authors.forename: Francisco Jose
authors.initials: FJ
authors.lastname: Rios
authors.affiliation: From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow (K.B.N., A.N.D.C., R.A.M.L., F.J.R., A.A., A.C.M., R.M.T.); Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N., A.M.d.O.) and Department of Pharmacology (R.A.M.L., R.C.T.), University of Sao Paulo, Ribeirao Preto, SP, Brazil; and Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil (N.S.L.).
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Anagnostopoulou
authors.affiliation: From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow (K.B.N., A.N.D.C., R.A.M.L., F.J.R., A.A., A.C.M., R.M.T.); Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N., A.M.d.O.) and Department of Pharmacology (R.A.M.L., R.C.T.), University of Sao Paulo, Ribeirao Preto, SP, Brazil; and Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil (N.S.L.).
authors.forename: Nubia Souza
authors.initials: NS
authors.lastname: Lobato
authors.affiliation: From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow (K.B.N., A.N.D.C., R.A.M.L., F.J.R., A.A., A.C.M., R.M.T.); Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N., A.M.d.O.) and Department of Pharmacology (R.A.M.L., R.C.T.), University of Sao Paulo, Ribeirao Preto, SP, Brazil; and Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil (N.S.L.).
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: de Oliveira
authors.affiliation: From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow (K.B.N., A.N.D.C., R.A.M.L., F.J.R., A.A., A.C.M., R.M.T.); Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N., A.M.d.O.) and Department of Pharmacology (R.A.M.L., R.C.T.), University of Sao Paulo, Ribeirao Preto, SP, Brazil; and Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil (N.S.L.).
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
authors.affiliation: From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow (K.B.N., A.N.D.C., R.A.M.L., F.J.R., A.A., A.C.M., R.M.T.); Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N., A.M.d.O.) and Department of Pharmacology (R.A.M.L., R.C.T.), University of Sao Paulo, Ribeirao Preto, SP, Brazil; and Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil (N.S.L.).
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Montezano
authors.affiliation: From the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, College of Medicine, Veterinary and Life Sciences, University of Glasgow (K.B.N., A.N.D.C., R.A.M.L., F.J.R., A.A., A.C.M., R.M.T.); Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N., A.M.d.O.) and Department of Pharmacology (R.A.M.L., R.C.T.), University of Sao Paulo, Ribeirao Preto, SP, Brazil; and Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil (N.S.L.). rhian.touyz@glasgow.ac.uk.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D018925:Chemokines / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; C478630:RARRES2 protein, human; D017382:Reactive Oxygen Species; D053148:Caspase 3
keywords: adipokines; diabetes mellitus; obesity; reactive oxygen species